PT98221B - PROCESS FOR THE PREPARATION OF NEW GUANIDINES AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM - Google Patents

Abstract

The novel guanidines of the formula <IMAGE> in which, L, M, R, T and X have the meaning given in the description, and hydrates or solvates thereof, inhibit thrombin-induced platelet aggregation and fibrinogen clotting in the plasma, are prepared by amidination, or by amide formation or esterification, depending on whether L is NH or O.

Description

PROCESS FOR THE PREPARATION OF NEW GUANIDINES

AND PHARMACEUTICAL COMPOSITIONS THAT CONTAIN THEM

The present invention concerns new guanidines of general formula

in which

R represents an aryl, heteroaryl or heterocyclic group,

T represents an oxygen atom or a CH ₂ group,

L represents an oxygen atom or an NH group,

X represents a hydrogen atom or a group

-CH ₂ COOH, -CH ₂ COO-C ^ _ ^alkyl, -CH ₂ CO- (tetra-hemethylethylimino) or -CH ₂ CONH ₂ optionally N-mono or N-di-alkylated with one (or two ) radical (s) al. kilo and

M represents a benzyl-OCONHCH ₂ CH = or -CH ₂ (benzyl-OCONH) CH- group or a group of general formula R '- (CH ₂ ) ₁ _ ₂ CH =, R'-COCH ₂ CH =, R- COCH ₂ CH =, R '(C0) ₁ _ ₂ NHCH ₂ CH =, -CH ₂ [R' - (CO) ₁ _ ₂ NH] CH- or -CH (CO-Q) CH ₂ - where R ' represents an aryl, heteroaryl, cycloalkyl or heterocyclic group, R represents a group

po tetrahydro comprising the heptametilenoimino, even tually up to two substituents selected from oxo, -COO-C ^ _ ₄ alkyl, - (CE ^) ^ θ_ ΟΗ-,

- (CH ₂ ) Q_ ^ OCO-C _1-4 alkyl, or carbamoyl, possibly containing one or two C ₄ _ ₄ , ® groups

Q represents a benzylamino group or tetra- Hep> tametilenoimino optionally interrupted by an oxygen or sulfur atom and having also optionally two substituents selected from alkyl C ^ _ _4, COOH, COO-C ^ _ ₄ alkyl, CH ₂ OH and -CH ₂ 0-benzyl; and

-N (X) -M- represents an eventual isoquinolylene group, substituting in the phenyl nucleus or a group of general formula -N (SO ₂ ~ Rq) -CH ₂ - in which Rg has the meanings previously defined for the symbol R, as well as their hydrates or solvation products and their physiologically acceptable salts.

The present invention relates to a process for the preparation of the aforementioned compounds, to the pharmaceutical compositions containing them, and to the use of these compounds in the preparation of pharmaceutical compositions.

Examples of physiologically acceptable salts of guanidines of the general formula I are salts derived from mineral acids which are also physiologically acceptable, such as hydrochloric acid, sulfuric acid, sulfuric acid or phosphoric acid; or derivatives of organic acids such as methanesulfonic acid, jo-toluenesulfonic acid, acetic acid, trifluoroacetic acid, citric acid, fumaric acid, maleic acid, taric acid

». Tantric, succinic acid or salicylic acid. Guanidines of general formula I with a free carboxylic group can also form salts with physiologically acceptable bases. Examples of such salts are alkali metal, alkaline earth metal, ammonium or alkylammonium salts, such as sodium, potassium, calcium or tetramethylammonium salts. Guanidines of general formula I may also be in the form of dipolar ions.

Guanidines of general formula I can be solvated, especially hydrated. Hydration can take place during the preparation process or it can occur gradually as a result of hygroscopic properties or due to a compound of formula I initially anhydrous.

Guanidines of general formula I contain at least two asymmetric carbon atoms and, therefore, can be in the form of mixtures of diastereomers or in the form of an optically pure compound.

Within the scope of the present invention an alkyl group means a straight or branched chain group such as, for example, a methyl, ethyl, propyl, isopropyl, butyl, isobutyl or t-butyl group.

term aryl means a phenyl, naphthyl or anthryl group possibly having 1 to 4 substituents chosen from halogen atoms or groups NO ^, NE ^, CN, hydroxy CH ^, isopropyl, t-butyl, phenyl, phenylsulfonyl, OCH ^, benzyloxy , formamide, COOH, COO-n-alkyl or possibly mono or di-alkylated amino containing the alkyl group (s) one to four carbon atoms.

Other possible substituents positioned in the group

phenyl are the groups of the general formula -NHSC ^ -Ar or -NHCO-Ar (where Ar represents a phenyl group with up to three substituents chosen from halogen atoms or groups NC ^, CFg, COOH or 0 _χ _ ₄ alkyl as , for example, a group “CH ^, -NHCOC ^ C ^ COO (H, C _x __ ₄ alkyl or benzyl), acetamido, NHCOCH ₂ OCH ₂ CH ₂ OCH ₃ , -NHCOO (H or 0 _χ _ ₄ alkyl) , -NHCOCOO (H or 0 _{χ 4} alkyl), -NHC ^ COO-ethyl, -NHCOCOCgH ₅ and tetra- heptamethyleneiminocarbonyl.

Cyclohexyl and decalyl groups are examples and cycloalkyl groups. Heteroaryl groups that are made up of one or two rings and contain 3 to 9 carbon atoms and 1 or 2 hetero atoms. Examples of such groups are imidazolyl, thienyl, benzothienyl, quinolyl and indolyl groups. These groups may contain substituents chosen from halogen atoms and CH2, -CH2 COOH and 1-methyl-5-trifluoromethyl-pyrazolyl groups.

heterocyclic term referring to groups having one or two nuclei, 4 to 7 carbon atoms and 1 or 2 hetero atoms such as, for example, tetrahydroquinolyl, azepinyl, piperidinyl, pyrrolidinyl, benzodiazepinyl, benzoxazolyl groups. or benzopyrrolidinyl having, eventually, one or two substituents chosen from halogen atoms and methyl, oxo, COOH and COOCH ^ - groups.

The piperidine, hexahydroazepine and heptahydroazocine groups are examples of tetra- to hepta.methyleneimino groups. The acetoxy, acetoxymethyl, carbomethoxy, caromethoxy, carb toxi, diethylcarbamoyl, butyryloxymethyl and isobutyryloxymethyl groups are examples linked to groups represented by the symbol R.

The carboxy-hexahydroxazepine and hexahydrothiaze groups

pin are examples of tetra-a heptamethyleneimino groups interrupted by a sulfur atom and containing, eventually, substituents.

Chlorine atoms and groups NC NEN ^ and OH are considered, for example, as substituents on the phenyl nucleus with respect to an isoquinolylene group of the general formula -N (X) -M.

Examples of compounds of general formula I are compounds of general formula

in which

-N (X ') - M'- represents an isoquinolylene group possibly substituted in the phenyl nucleus, or

X 'represents a hydrogen atom or a group

-CH ₂ COOH, -CH ₂ COO-alkyl 0 _χ _ ₄ , -CH ₂ CO- (tetra- heptamethyleneimino) or -CH ₂ CONH ₂ possibly N-mono or N-di-alkylated with one (or two) groups ^ _ ₄ alkyl and

M 'represents a group of general formula R' - (CH ₂ ) ^ _ ₂ CH = R'-COCH ₂ CH = or -CH (CO-Q ') ch ₂ ,

Q 'represents a benzylamino, morpholino or tetra-heptamethyleneimino group, and

R, R ', L and T have the meanings defined above, as well as their hydrates or solvation products and physiologically acceptable salts.

Preferred compounds among the compounds of general formula IA are those in which X 'represents a hydrogen atom and R, M', L and T have the meanings defined above.

Preferred compounds among the compounds of the general formula I are the compounds of the general formula

in which

M represents a benzyl-OCONHCH ₂ CH = group or

-CH ₂ (benzyl-OCONH) CH- or a group of the general formula r-coch ₂ ch =, r '- (co) ₁ _ ₂ nhch ₂ ch =,

-ch ₂ [r ¹ - (co) ₁ _ ₂ nh] ch- OR -ch (co-q) ch ₂ -,

Q represents a tetra- to heptamethyleneimino group which may be interrupted by an oxygen or sulfur atom and possibly containing up to two substituents chosen from alkyl groups such as ^ 14 'COOH, -COO-alkyl C4 _ ^, -CH ^ OH and C1 ^ O -benzyl, and

R, R ', R, L and T have the meanings defined before.

The naphthyl, hydroxynaphthyl, 4-biphenyl, 2-anthryl groups

lo, iodophenyl, nitrophenyl, benzyloxyphenyl, dimethoxyphenyl, 4-methoxy-2,3,6-trimethylphenyl, 2,4,6-triisopropylphenyl, carboxyphenyl, methoxycarboniphenyl, benzyloxyphenyl, phenylsulfo-nylphenyl, hexa-hydroxy-phenyl-butylphenyl-phenylphenyl-phenylphenyl aryl groups represented by the symbol R.

The 3-methyl-8-quinolyl, 5- (1-methyl-5-trifluoro methylpyrazol-3-yl) -2-thienyl and benzothienyl groups are examples of heteroaryl groups represented by the symbol R.

3-methyl-1,2,3,4-tetrahydro-8-quinolyl group is an example of a heterocyclic group represented by the symbol R.

N-dimethylaminonafty-sulfonylaminomethylene group is an example of a sulfonamide group of general formula -N (SO ₂ Rq) ~ represented by the group of general formula -N (X) -M-,

Preferred compounds of the general formula I are those where X represents a hydrogen atom or a group

-ch ₂ cooh.

When M represents a group of general formula R '- (CH ₂ ) ^ _ ₂ CH =, examples of these groups are 3-indolylethylidene, 2,3-dioxo-1-indolinylethylidene, phenethylidene,

1,4-dioxo-5H-2,5-benzodiazepin-5-ylethylidene, (fluorine, chlorine, iodine, cyano, amino, carboxy, alkoxy (C ^ _ ^) - carbonyl or hydroxy-phenethylidene, cyclohexyl-propylidene , decalylethylidene, imidazolylethylidene, thienylethylidene, (methyl, bromine, fluorine or carboxymethyl) -3-indolylethylidene, naphthylethylidene, (ethoxycarbonyl-carbonylamino, methoxycarbonylethyl-carbonylamino, benzyloxycarbonylethyl-amylamoyl-carbonylamino-carbonylamino-carbonylamino-carbonylamino-carbonylamino-carbonylamino, carbo xicarbonylamino, carboxypropionylamino, tolyl sulfonamide, iodine

phenylsulfonamido, carboxyphenylsulfonamido or ethoxycarbonyl-methylamino-phenethylidene, oxobenzoxazolinetylidene or 5-bro mo- or 5-methyl-2,3-dioxo-1-indolinylethylidene.

When M represents a group of general formula (R ¹ or R2 COCH ₂ CH = examples of this group are the hexahydroazepinoethylidene, (methoxycarbonyl or carboxy) -pyrrolidinoethylidene 3,4-dihydro-2 (1H) -isoquinolinoethylidene, ( nitro, amino, iodine or formamide) -benzylethylidene, morpholinoethylidene, hepta -hydroazocinoethylidene, (ethoxycarbonyl, acetoxymethyl, dimethyl. carbamoyl, isobutyryloxymethyl or butyryloxymethyl) -piperidinoethylidene, 3-methoxy-ethyl-4-methoxy-ethyl -piperidinoethylidene.

When M represents a group of the general formula R '- (CO) i ₂ -NHCH ₂ CH =, examples of these groups are the benzoylcarboxamidoethylidene, thienoyl carboxamidoethylidene, benzoylamidoethylidene or benzyloxycarboxamidoethylidene groups.

When M means a group of the general formula -CH ₂ [R · - (CO) i_ ₂ NH] CH-, examples of these groups are groups 2- (carboxybenzoylamido] -ethylene, 2- (benzyloxybenzoylamido) -ethylene, 2- ( 2-piperidinecarboxamido) -ethylene, 2- (hydroxybenzoylamido) ethylene and 2- (aminobenzoylamido) -ethylene.

When M represents a group of the general formula -CH (CO-Q) CH ₂ -, examples of these groups are groups 1- (benzyl aminocarbonyl) -ethylene, 1- (hexahydroazepinoyl) -ethylene,

1- (morpholinoyl) -ethylene, 1- (heptahydroazocinoyl) -ethylene,

1- [2- (benzyloxymethyl-morpholinyl)] - ethylene, 1- [2- (hydroxymethyl-morpholinyl)] - ethylene, 1- (2-ethoxycarbonyl) -4-methyl-piperidinoyl) -ethylene, 1- (2- carboxy-4-methyl-piperidinoyl) -ethylene and 1- (3-carboxy-hexahydro-1,4-oxazepinoyl) -ethylene.

In the foregoing general formulas R preferably represents an aryl group, especially a naphthyl or nitro- or iodophenyl group; L preferably represents an NH group and the asymmetric carbon atom in the piperidine or morphine folin nucleus is preferably in the (S) configuration.

Preferred compounds of the general formula I are also the compounds of the general formula

in which

A represents an aryl, aroyl or heterocyclic group, especially a phenyl, nitrophenyl, indolyl, 2,3-dioxo-1-indolinyl or aminobenzoyl group.

The following examples are preferred compounds:

(R) -N - [(RS) -1-amidino-3-piperidinyl-methyl] - - (2-naphthylsulfonamido) -2,3-dioxo-1-indolinopropionamide, (R) -N - [(RS) - l-amidino-3-piperidinyl-methyl] ~ θ (~ (2-naphthylsulfonamido) -o-nitrohydrocinamamide, (R) -N - [(RS) -l-amidino-3-piperidinyl-methyl] - θ ( - (o-nitrobenzenesulfonamido) indole-3-propionamide, (R) -N - [(S) -1-amidino-3-piperidinyl-methyl] - - (p-iodo10 • «V benzenesulfonamido) indole-3-propionamide, (R) -N- [(S) -1-amidino-3-piperidinyl-methyl] - - (p-iodobenzenesulfonamido) -p-nitrohydrocinamamide, (R) -N - [(RS) -l-amidino- 3-piperidinyl-methyl] -3- (o-aminobenzoyl) - (2-naphthylsulfonamido) propionamide,

N - [(R) - - [[(S) -l-amidino-3-piperidinyl] methyl-carbamoyl] -fenethyl] -N- (2-naphthyl-sulfonyl) glycine, (R) -N - [( S) -l-amidino-3-piperidinyl-methyl] -1,2,3,4-tetrahydro-2- (2-naphthylsulfonyl) -3-isoquinolinocarboxamide, (S) -N - [(RS ) -l-amidino-3-piperidinyl-methyl] -hexa-hydro- (2-naphthyl-sulfonamido) -0 -oxo-1H-azepinobutyramide, (R) -N - [(S) -l-amidino-3- piperidinyl-methyl] - - (2-naphthylsulfonamido) -2,3-dioxo-1-indolinopropionamide, acid 4 ¹ - [(R) -2 - [[[[(S) -l-amidino-3-piperidinyl] methyl] carbamoyl] -2- (2-naphthyl-sulfonamido) ethyl] oxanyl, (S) -N - [[(RS) -1-amisino-3-piperidinyl] methyl] hexahydro - 2-naphthyl-sulfonamido- - oxo-1 (2H) -azocinobutyramide,

no, 4 ¹ - [(R) -2 - [[[((S) -1-amidino-3-piperidinyl] methyl] carbamoyl] -2- (2-naphthylsulfonamido) ethyl] succinanilic acid.

The compounds mentioned above can be prepared

a) by reacting an acid of general formula

R-SO ₂ N (X) -M-COOH (II) with intermediate protection of a carboxyl group present

in the group represented by the symbol X, R or M, with an amine or an alcohol of general formula

R — S — N — M — C — L II 1 11

X 0 (III) or a salt thereof, or

b) reacting a compound of general formula

(IV) with an amidation reagent or

c) reacting an amine of general formula

with an acid of the general formula R'-COOH or a functional derivative thereof,

d) modifying, eventually, the function of a reactive group present in the groups represented by the symbol M in a compound of general formula I, and

e) eventually converting a compound of formula I into a physiologically acceptable salt thereof or converting a salt of a compound of formula I into acid or free bases.

Appropriately, an acid of formula II is reacted in a solvent, such as dimethylformamide (DMF), at room temperature and in the presence of a base such as, for example, 4-ethylmorpholine or ethylldiisopropylamine, with a salt of a compound of general formula III, such as a trifluoroacetate, a bisulfite, a nitrate, a hydrochloride or a benzotriazol-1-yloxy-tris (dimethylamino) -phosphonium iodhydrate and hexafluorophosphate. Consequently, the protected carboxyl group, such as, for example, the t-butyl ester, present in the group represented by the symbol X, R or M, is released.

In process variant b), a

compound of general formula IV in a solvent such as, for example, dimethylformamide, in the presence of a base, such as triethylamine, with formamidinosulfonic acid or 3,5-dimethyl-1-pyrazolyl-formamidine nitrate at a temperature up to 50 ° C.

According to process variant c), an amine of general formula V can be reacted with an acid of general formula R'-COOH or a functional derivative thereof, such as an acid anhydride, within a solvent, such as dimethylformamide, in the presence of a base such as, for example, 4-ethylmorpholine, at an elevated temperature, for example up to 50 ° or 80 ° C.

The following indications are referred to as functional modifications of variant d):

1. - The reduction of a nitroaryl group present in the group represented by the symbol M in an aminoaryl group using palladium on charcoal in a solvent, such as ethanol.

2. - The saponification of an ester group, such as an ethoxicarbonyl group, for example in ethanol or methanol using a base, such as an aqueous sodium hydroxide solution;

3. - The saponification of an ester group, such as a benzyloxycarbonyl, for example, in ethanol using palladium on carbon;

4. - The fission of a benzyl ether, for example, in ethanol using palladium on charcoal in the presence of an acid, such as hydrochloric acid or acetic acid.

The N-sulfonated amino acids of general formula II can be prepared by reacting a reactive derivative of the corresponding sulfonic acid * such as a sulfonyl chloride of the general formula R-SC ^ Cl with the corresponding free amino acid of the general formula HN (X ) -M-COOH in the presence of a base such as, for example, an alkali metal hydroxide in a solvent, such as an ether, for example, ethyl ether or dioxane, and water.

In a variant, an acid of general formula II can be prepared by oxidation of the corresponding alcohol of general formula

R-SO ₂ -N (X) -M-CH ₂ OH (VI) for example, in a solvent, such as acetone, with an oxidizing agent such as, for example, Jones reagent. At the same time, a heterocyclic radical represented by the symbol R 'is oxidized, such as, for example, the group 2-oxo-1-indolinyl, present in the group represented by the symbol M of an alcohol of general formula VI, resulting in a group 2,3- dioxo-1-indolinyl.

An alcohol of general formula VI can be prepared by reacting the corresponding -amino-alcohol of general formula HN (X) -M-CH ₂ OH in the presence of an aqueous solution of sodium hydroxide and sodium hydrogen carbonate with a chloride of sulfonyl of the general formula R-SO ₂ C1 in dioxane.

An amino alcohol of the general formula HN (X) -M-CH ₂ OH in which M represents, for example, a group of the general formula -CH (CH ₂ -R ') can be prepared by splitting the corresponding protected oxazolidine group in the nitrogen atom and having as a substitute in position 4 a group of the general formula -CH ₂ -R ', for example, the group (R) -2,2-dimethyl-4- (CH ₂ -R') - T-butyl 3-oxazolidinecarboxylate, with hydrochloric acid in methanol.

The aforementioned oxazolidine can be prepared in a manner known per se, for example, when R 'represents a heterocyclic radical attached via a nitrogen atom, such as a 2-oxo-1-indolinyl group, by reacting to corresponding cyclic amine of general formula HR 'with t-buti (S) -2,2-dimethyl-4- (t-butyl-sulfonyloxymethyl) -3-oxazolidinecarboxylate.

in the presence of a suspension of sodium hydride in dimethij. formamide.

For the preparation of an amino acid of the general formula in which R represents a hydroxyaryl radical, the corresponding sulfonyl carbide of the general formula R-SC ^ Cl is reacted first in which the hydroxy group is present in a protected form, for example. example, in the form of an acetoxy group, in acetone with an amino acid of general formula

HN (X) -M-COOH in the presence of an aqueous sodium hydroxide solution and then the protecting group, for example an acetyl group, is removed with a solution of sodium hydroxide in water and methanol.

For the preparation of a guanidine with a general formula in which X represents a -CE ^ COOH group, a sulfonyl chloride of the general formula R-SC ^ Cl is first reacted with a salt, for example, t-toluenesulfonate , of an H 2 NM-COO-benzyl ester in a solvent, such as methylene chloride and in the presence of a base such as, for example, triethylamine. Then, the resulting sulfonamide of the general formula R-SO ₂ NH-M-C00C-benzyl is reacted with t-butyl bromoacetate in a solvent, such as tetrahydrofuran at a temperature close to -80 ° C in the presence of bu

til lithium. Then, the benzyl group is selectively removed, for example, by catalytic hydrogenation with palladium on carbon in ethanol, from the resulting diester of the general formula

R-SO ₂ n (CH ₂ COO-t-butyl) -M-COO-benzyl

As described above, in the reaction of the resulting acid with a compound of formula III, the carboxyl group present in the side chain is released, which is protected as a t-butyl ester.

The initial acid compounds of the general formula R-SO ₂ NHCH (CO-Q) -CH ₂ COOH can be prepared

a) Reacting an aspartic acid derivative such as t-buto.xi-CONHCH (COOH) CH ₂ COO-benzyl with an amine of the general formula HQ corresponding to the group Q 'in a solvent such as, for example , dimethylformamide and in the presence of benzotriazol-1-yloxy-tris (dimethylamino) -phosphonium hexafluorophosphate.

(b) by reacting the resulting t-butoxy-CONHCH (CO-Q) -CH ₂ COO-benzyl amide in a solvent, such as ethyl acetate, as an acid such as, for example, hydrochloric acid and then in dioxane with sodium hydroxide, sodium hydrogen carbonate and a sulfonyl chloride of the general formula R-SO ₂ CL, and

c) Removing the benzyl group from the resulting sulfonamide R-SO ₂ NHCH (CO-Q) -CH ₂ COO-benzyl in a solvent, such as methanol, using a sodium hydroxide solution.

The compounds of general formulas III, IV and V are new and as such are the subject of the present invention. Piperidine derivatives of general formula III can be prepared according to the techniques described in Examples 1, 2 and 3, which follow, from 3-picolylamine where L represents an NH group or from 3-hydroxymethyl -piperidine in which L represents an oxygen atom. The aminomethyl-morpholine derivatives of general formula III are obtained by reacting 2-aminomethyl-4-benzyl-morpholine. [Jí · Med. Chem., 33 (1990) 1406-1413] with di-t-butyl dicarbonate in dioxane, hydrogenating the resulting Boc-protected amine in ethanol and in the presence of palladium on coal, for obtaining 2- (t-butoxy bonylaminomethyl) -morpholine and amidating the latter compound. Hydroxymethyl-morpholine derivatives of general formula III can be prepared by amidation of 2-hydroxymethyl-morpholine.

Compounds of general formula IV are prepared by reacting the corresponding acid of general formula II with a compound of general formula

(III ¹ ) in which

W represents a protecting group such as a Boc group or a group represented by the symbol Z, for example, as described above for the reaction of a compound

post of general formula II with a compound of general formula III, followed by the removal of the protecting group, for example, using trifluoroacetic acid in methylene chloride, jo-toluenesulfonic acid in acetonitrile or a solution of hydrochloric acid in of ethyl acetate.

The alcohols of general formula III 'can be prepared according to the technique described in Example 3a) by introducing the protecting group in the nitrogen atom of the radical 3-hydroxymethyl-piperidine or according to the technique described in Example 19a) to e) from benzyloxymethyloxirane via 2-benzyloxymethyl-morpholine and, for example, Boc-protected 2-benzyloxymethyl-morpholine. The resulting alcohol can then be converted to the corresponding amine of general formula III 'according to the technique described in Examples 6a) to d) and 19d) to E).

The amines of general formula V can be prepared by removing the benzyloxycarbonyl group from the corresponding compound of general formula I in which M represents, for example, a -CE ^ (benzyl) -OCONH) CH- group, for example, within of ethanol using palladium on charcoal in the presence of hydrochloric acid.

Guanidines of general formula I, their solvation products and their salts inhibit not only thrombin-induced aggregation, but also coagulation induced by plasma fibrinogen thrombin. The compounds mentioned above influence not only platelet-induced aggregation, but also plasma clotting. Consequently, these compounds especially prevent the formation of hyaline clots and platelet-rich clots and can be used in

19 control or prevention of diseases such as, for example, thrombosis, cerebrovascular accidents, cardiac infarction, inflammation and arteriosclerosis. These compounds also act on tumor cells preventing the formation of metastases. Under these conditions, they can also be used as anti-tumor agents.

Differential inhibition of thrombin and other serine proteases by the desired compounds above is desirable, in order to obtain compounds with as high specificity as possible and at the same time to avoid possible side effects. In parallel, with other tested serine proteases, the relationship between trypsin inhibition and thrombin inhibition was considered as the general evaluation for the specificity of a compound (referred to as q in the table below), because trypsin is serine. less specific protease, can be easily inhibited by a wide variety of inhibitors. In order for thrombin inhibitions to be directly comparable, despite the use of different substrates, constant Ki inhibition was determined regardless of the substrate and enzyme concentration as a measure of inhibition.

To determine the inhibition of the catalytic activity of the aforementioned proteases, specific chromogenic peptide substrates can be used. The inhibition of thrombin and trypsin amidolytic activity by the above mentioned guanidines was determined according to the technique described below.

Measurements were performed on microtiter plates at room temperature. For this purpose, they were mixed in

plate activity 150 µl of buffer (50 mM Tris, 100 mM sodium chloride, 0.1% polyethylene glycol; pH 7.8) with 50 µl of the inhibitor dissolved in dimethylsulfoxide and diluted in the buffer and added 25 µl of human thrombin (final concentration 0.5nM). After incubation for 10 minutes, the reaction was started by adding the chromogenic substrate S-2238 (HD-Phe-Pip-Arg-para-nitroaniline supplied by Kabivitrum; final concentration of 10 or 50 µm) followed by hydrolysis of the substrate by spectrophotometry using a microtiter plate piglet for 5 minutes. After obtaining the inhibition curves, the H values were determined; according to the method described in Biochem., J, 55 (1955) 170-171. The trypsin inhibition was carried out in an analogous manner but using the substrate S-2251 (H-D-Val-Leu-Lys-para-nitroaniline) in a final concentration of 200 and 750 µM.

The following table shows the results:

Product Example 8 9 13a 14i 17b (nM) Thrombin 8.55 135 20.8 25 20.7 K _± (nM) Trypsin 20075 168700 29200 38000 6300 q 2350 1250 1400 1520 304

Product Example 17c 17f 17 j 18f IC (nM) Thrombin 58 41.3 26.1 16 K _± (nM) Trypsin 10000 18300 14800 18850 q 172 455 565 1180

-21Guanidines of general formula I have low toxicity. Thus, the products of Examples 8, 13a, 14 i and 18f exhibit a DL ^ g of between 30 and 50 mg / kg in the mouse after intravenous administration.

As mentioned above, mediations containing a guanidine of general formula I, a solvation product or a salt thereof are also the subject of the present invention, as well as a process for the preparation of these drugs which consists of incorporating one or more of the aforementioned compounds and, eventually, one or more other substances with therapeutic value in a galenic dosage form. These drugs can be administered enterally, for example, orally in the form of coated tablets, dragees, soft and hard gelatin capsules, solutions, emulsions or suspensions or rectally, for example in the form of suppositories, or in the form of spray. However, administration can also be carried out parenterally, for example, in the form of injectable solutions.

For the preparation of tablets, coated tablets, dragees and hard gelatin capsules, the active substance can be mixed with pharmaceutically inert or organic excipients. Lactose, corn starch or its derivatives, stearic acid or its salts are examples of such excipients used in tablets, coated tablets, dragees and hard gelatin capsules. Excipients suitable for preparing gelatin capsules are, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols; however, depending on the nature of the active substance, excipients are generally not required.

when preparing soft gelatin capsules. Excipients suitable for the preparation of solutions and syrups are, for example, water, polyols, sucrose, invert sugar and glucose; excipients suitable for injectable solutions are, for example, water, alcohols, polyols, glycerol and vegetable oils; and excipients suitable for the preparation of suppositories are natural or hardened oils, waxes, fats, semi-liquid or liquid polyols. Pharmaceutical preparations. They may also contain preservatives, solubilizing agents, stabilizing agents, moisturizing agents, emulsifiers, sweeteners, colorants, flavorings, salts that allow osmotic pressure to vary, buffers, coating agents or anti-oxidants.

For the control or prevention of the aforementioned diseases, the dosage of the active substance can vary between very distant limits, being established, of course, according to the individual requirements in each particular case. In general, in the case of oral or parenteral administration, a dose between approximately 0.1 and 20 mg / kg, preferably between approximately 0.5 and 4 mg / kg, per day, should be appropriate for adults, although the limit exceeded may be exceeded when convenient.

Example 1

a) To a solution of 30 g of 3-picolylamine in 300 ml of dioxane is added another solution of 66.6 g of di-t-butyl dicarbonate in 200 ml of dioxane so that the temperature does not exceed 25 ° C. The reaction mixture is stirred for 3 hours at room temperature and evaporated. After filtration on silica gel with ethyl acetate, 55.5 g of 3-t-butyloxycarbonyl-picolylamine are obtained.

b) In 220 ml of methanol, 45.5 g of 3-t-butyloxy are dissolved. carbonyl-picolylamine and is catalytically hydrogenated with 4.6 g of 5% ruthenium on aluminum, at a temperature of 60 ° C and under a pressure of hydrogen of 100 bar. After filtering the catalyst and evaporating the solvent, 46 g of racemic 3-t-butyloxycarbylaminomethyl-piperidine are obtained.

c) In 900 ml of dimethylformamide, 38.8 g of the product prepared in b) are dissolved and treated with 74.5 ml of triethylamine.

After the addition of 26.5 g of formamidinosulfonic acid, the reaction mixture is stirred for 15 hours, after which it is filtered. The stock solution is evaporated and the residue is taken up in water and extracted with ethyl acetate. The aqueous phase is evaporated and the product is evaporated by forming a trophic olive mixture with ethanol, toluene and dichloroethane. The residue is suspended in ether and filtered. 44.0 g of racemic 3-t-butoxycarbonylaminomethyl-1-amidinopiperidine hemisulfite are obtained. MS: 257 (M ⁺ + 1), 201, 157, 126.96.

d) In 70 ml of methylene chloride, 27.8 g of the product obtained in e) are dissolved, treated with 70 ml of trifluoroacetic acid at 0 ° C and stirred for 1 hour. The reaction mixture is evaporated and the residue is evaporated by forming an azeotropic mixture with toluene and ethanol. Ob 27.6 g of racemic 3-aminomethyl-1-amidinopiperidine sulfite are obtained. MS: 156 (M ⁺ + 1), 126 (M ^ -C ^ NE ^), 69.45.

, Example 2

A solution of 5.3 g of racemic 3-hydroxymethylpiperidine in 100 ml of dimethylformamide is treated with 19 ml of triethylamine. After the addition of 6.8 g of formamidinosulfonic acid, the reaction mixture is stirred for 15 hours. The suspension is filtered and the precipitate is washed with ether and dried. Obtain 10.3 g of racemic 3-hydroxymethyl-1-aminopiperidine hemisulfite. E.M .: 158 (M + 1), 143, 116, 102 M.P .: 100 ° C.

Example 3

A) To a solution of 92.9 g of 3-hydroxymethyl-piperidine in 1500 ml of dioxane is added a solution of 211.2 g of di-t-butyl dicarbonate in 500 ml of dioxane so that the temperature do not exceed 25 ° C. The reaction mixture is stirred for 15 hours at room temperature and evaporated. The residue is suspended in 800 ml of hexane and filtered. 120.7 g of racemic N-t-butyloxycarbonyl-3-hydroxymethyl-piperidine are obtained. P. F .: 78 ° C.

b) A solution of 100 g of the product prepared in a) in 4000 ml of methylene chloride is treated with 56.2 ml of pyridine and the air is cooled to 0 ° C. 58.3 ml of butyryl chloride are added dropwise so that the temperature does not exceed 10 ° C. The reaction mixture is then stirred for 15 hours at room temperature. The suspension is filtered, the filtrate is evaporated and the residue is taken up in ethyl acetate. The organic phase is washed with a 10% aqueous solution of copper sulphate, dried and evaporated. The residue is filtered

-25 through silica gel and elute with a mixture of hexane / ethyl acetate (8: 2). 119.7 g of racemic t-butyl 3- (butyroxymethyl) -1-piperidinecarboxylate are obtained.

c) In 2 liters of a 0.1M sodium chloride solution and 80 ml of sodium phosphate buffer, pH 7.0, 116.6 g of the product prepared in b) are emulsified. The pH is stirred to 7.0 with a Ι, ΟΝ solution of sodium hydroxide and the reaction is started by adding 1.00 g of lipoprotein-lipase produced by Pseudomonas fluorescens (lipase P-30, Amano) in 10 ml of a 0.1M sodium chloride solution. The pH is maintained at 7.0 by adding a 2.0N sodium hydroxide solution, with stirring. After 14 hours the reaction is stopped by adding 500 ml of methylene chloride, the reaction mixture is extracted with methylene chloride and the organic phase is dried and evaporated. Chromatography of the residue on silica gel. using a hexane / ethyl acetate mixture as eluent gives 36.6 g of t-butyl [s] -3-hydroxymethyl-1-piperidinecarboxylate. M.P .: 89 ° -90 ° C, [^ 1 ^ = + 53.5 ° (C = 1.0, ethanol).

d) In 1.15 liters of a 0.1 M sodium chloride solution and 45 ml of 0.1 M sodium phosphate buffer (pH 7.0), 65.7 g of the ester fraction prepared in c) are emulsified and treat with 0.50 g of Lipase P-30 in 5 ml of a 0.1 M sodium chloride solution. The pH is maintained at 7.0 by adding a 2.0N sodium hydroxide solution while stirring. After 40 hours, the reaction is stopped by adding 400 ml of methylene chloride, the reaction mixture is extracted with methylene chloride and the organic phase is dried and evaporated. A chromatography of the residue on silica gel using as eluen

a mixture of hexane / ethyl acetate gives 49.5 g of t-butyl [R] -3- (butyryloxymethyl) -1-piperidinecarboxylate. This product is dissolved in 250 ml of ethanol, treated with 88 ml of a 2N sodium hydroxide solution, stirred overnight and then evaporated. The residue is taken up with 200 ml of methylene chloride and washed with water, the aqueous phase is extracted with methylene chloride and the organic phase is dried and concentrated. Chromatography of the residue on sj gel. logic using a hexane / ethyl acetate mixture as eluent gives 33.7 g of t-butyl [R] -3-hydroxymethyl-1-piperidinecarboxylate. = -60.7 ° (c = 1.0, ethanol).

365

e) A solution of 5.0 g of the product prepared in d) in 20 ml of methylene chloride is cooled to 0 ° C and treated with 15 ml of trifluoroacetic acid. After 2 hours, the reaction mixture is evaporated and the residue is taken up in water and then treated with sodium hydrogen carbonate to pH 7.5. The aqueous phase is evaporated and the crystalline mass is suspended in 100 ml of methylene chloride / ethanol (9: 1). Ots are separated by filtration and the filtrate is evaporated. The residue is dissolved in 30 ml of dimethylformamide and treated with 9.7 ml of triethylamine. After the addition of 3.5 g of formamidinesulfonic acid, the reaction mixture is stirred for 15 hours. The precipitate is filtered off and the solvent is evaporated. The residue is purified by reverse phase chromatography on silylated silica gel, RP-18 with water. 2.6 g of (R) -3-hydroxymethyl-1-amidinopiperidine hemisulfate are obtained. E.M.-FAB: 158 (M + 1).

27Example 4 ·, w

From (S) -3-hydroxymethyl-1-piperidinecarboxylate of t-butyl, using a technique similar to that described in Example 3e), the (S) -3-hydroxymethyl-1-amidinopiperidine hemisulfate is prepared. E.M .: FAB: 158 (M + 1).

Example 5

A solution of 1.5 g of N- (2-naphthylsulfonyl) -D-tryptophan in 30 ml of dimethylformamide is treated with 1.5 ml of ethylmorpholine. After the addition of 0.7 g of racemic 3-aminomethyl-1-amidinopiperidine sulfite (Example 1) and 1.7 g of benzotriazol-1-yloxy-tris hexafluorophosphate (dimethylamino-foj; phonium), stir the reaction mixture for 15 hours. Evaporate the solvent and take up the residue with 50 ml of water and extract with 100 ml of ethyl acetate. Wash the ethyl acetate layer with water, dry and evaporate. The crude product is purified on an RP-18 column using water / acetonitrile (0-30%) as eluent. 0.8 g of (R) -N - [(RS) -1-amidino-3-piperidinyl-methyl] - - (2-naphthyl-sulfonamido) -indol-3-propionamide bisulfite are obtained. E.M.:- FAB: 533 (M + H).

Example 6

a) Treat a solution of 5.0 g of t-butyl (S) -3-hydroxymethyl-1-piperidinecarboxylate (Example 3c) in 100 ml of pyridine with 5.4 g of β-chlorosulfonyl chloride. The reaction mixture is stirred for 15 hours, evaporated, taken up with 200 ml of ethyl acetate and washed with water and a 10% aqueous solution of copper sulphate. The organic phase is dried.

28ca and evaporate. Filter the residue over silica gel uti. using as eluent hexane / ethyl acetate (8: 2). 6.5 g of t-butyl (S) -3- (jo-chlorophenyl-sulfonyloxymethyl) -1-piperidinecarboxylate are obtained.

b) A solution of the product prepared in a) in 50 ml of dimethylformamide is treated with 3.25 g of sodium azide. The reaction mixture is stirred for 15 hours at 50 ° C and evaporated. The residue is taken up with water and ether and washed with water. The ethereal phase is dried and evaporated. 4.0 g of t-butyl (S) -3-azidomethyl-1-piperidinecarboxylate are obtained.

<

c) A solution of the product prepared in b) is hydrogenated in

100 ml of ethanol, in the presence of 0.6 g of platinum oxide and under a pressure of 1 bar of hydrogen. The reaction mixture is then filtered over silica gel using methanol as eluent. 3.4 g of t-butyl (R) -3-aminomethyl-1-piperidinecarboxylate are obtained. [^] ² ^ = + 23.0 ° (c = 0.4 ethanol).

d) Using a similar process, from t-butyl (R) -3-hydroxymethyl-1-piperidinecarboxylate, t-butyl (S) —3 -aminomethyl-1-piperidinecarboxylate is obtained. [¢ (] -17.7 ° (c = 0.6, ethanol).

e) Treat a solution of 1.5 g of N- (2-naphthylsulfonyl) -D-tryptophan in 50 ml of dimethylformamide with 0.8 ml of ethildiisopropylamine. After adding 1.0 g of the product prepared in d) and 1.7 g of benzotriazol-1-yloxy-tris (dimethylamino) -phosphonium hexafluorophosphate, the reaction mixture is stirred for 15 hours. Evaporate the solvent and take up the residue with water and extract with ethyl acetate. Wash up

the ethyl acetate phase with water, dried and evaporated. Chromatography on silica gel eluting with ethyl acetate gives 2.3 g of (R) [(S) -1- (t-butyloxycarbonyl) -3-piperidinylmethyl] -naphthylsulfonamidoindole-3-propionamide.

f) A solution of the product prepared in point (e) is treated in 10 ml of methylene chloride, at 0 ° C, with ml of trifluoroacetic acid. The reaction mixture is stirred for 1 hour at 0 ° C, evaporated and an azeotropic mixture is formed with the residue and ethylene chloride. The residue is taken up with water and ethyl acetate, the pH is adjusted to 9 with 10% sodium carbonate and extracted. The organic layer is dried and evaporated. 2.5 g of (R) - naphthyl sulfonamido-N - [(S) -3-piperidinylmethyl] -indol-3-propionamide are obtained.

g) A solution of the product prepared in f) in 50 ml of dimethylformamide is treated with 1.7 ml of triethylamine. After adding 0.7 g of formamidinesulfonic acid, the reaction mixture is stirred for 15 hours. Evaporate the solvent and take up the residue with ethyl acetate and methanol. Wash the organic phase with water, dry and evaporate. Purification of the product on an RP-18 column, using water / acetonitrile as eluent, gives 1.75 g of (R) -N - [(S) -1-amidino-3-piperidinylmethyl] - ¢ (- (2 -naphthyl-sulfonamido) -indol-3-propionamide EM-FAB: 533 (M + H).

Example 7

a) Treat a solution of 1.0 g of Ν-2-naphthylsulfonyl- (D) -tryptophan in 20 ml of dimethylformamide with 0.5 ml of ethildi. isopropylamine. After adding 0.6 g of t-butyl (S) -3-hydroxymethyl-1-piperidinecarboxylate (Example 3c) and 1.1 g of benzotriazol-1-yloxy-tris (dimethylamino) -phosphonium hexafluorophosphate, stir the reaction mixture for 15 hours. Evaporate the solvent and take up the residue with water and extract with ethyl acetate. Wash the ethyl acetate layer with water, dry and evaporate. Chromatography on silica gel using ethyl acetate as the eluent gives 1.0 g of the N- (2-naphthylsulfonyl) -D-tryptophan (S) -1-t-butyloxycarbonyl-3-piperidinylmethyl ester.

b) A solution of the product obtained in (a) in 10 ml of acetonitrile is treated with 0.9 ml of Î ± -toluenesulfonic acid. The reaction mixture is stirred for 15 hours. After evaporation, the residue is treated with ethyl acetate and washed with a saturated solution of sodium hydrogen carbonate. The organic layer is dried and evaporated. Purification on a useful RP column. Using water / acetonitrile as eluent gives 0.47 g of N- (2-naphthylsulfonyl) -D-tryptophan (S) -3-piperidinylmethyl ester.

c) A solution of the product prepared in (b) in 20 ml of dimethylformamide is treated with 0.4 ml of triethylamine. After the addition of 0.2 g of formamidinesulfonic acid, the reaction mixture is stirred for 15 hours. The dimethylformamide is evaporated and the residue is taken up with ethyl acetate and washed with water. The organic phase is dried and evaporated. Purification on an RP column using water / acetonitrile as eluent gives 0.27g of N- (2-naphthyl-sulfonyl) -D-tryptophan (S) -1-amidino-3-piperidinylmethyl ester bisulfite. FAB-MS: 534 (M + 1).

Example 8

a) Treat a solution of 10.7 g of t-butyl (R) -4-hydroxymethyl-2,2-dimethyl-3-oxazolidinecarboxylate [J. Org. Chem., 52 (1987) 2361-64] in 107 ml of pyridine, with 9.7 g of β-toluenesulfonyl chloride. The reaction mixture is stirred for 17 hours, after which time it is taken up with ethyl acetate and washed with water. After drying and evaporation, the residue is purified on silica gel using hexane / ethyl acetate (3: 1) as eluent. 15.1 g of t-butyl (S) -2,2-dimethyl-4- (jo-tolyl-sulfonyloxymethyl) -3-oxazolidinecarboxylate were obtained.

b) To a suspension of 0.82 g of sodium hydride in 50 ml of dimethylformamide, 4.6 g of 2-indolinone are added and the mixture is stirred for 90 minutes. Then 6.6 g of the product prepared in (a) in 60 ml of dimethylformamide are added and the reaction mixture is stirred overnight at 50 ° C. After evaporation of the solvent, the residue is taken up in ethyl acetate and washed with water. After drying and evaporation of the solvent, the residue is purified on silica gel using ethyl acetate / hexane (1: 4) as eluent. 2.5 g of t-butyl (R) -2,2-dimethyl-4- (2-oxo-1-indolinyl-methyl) -3-oxazolidinecarboxylate are obtained.

c) Treat a solution of 2.5 g of the product prepared in subparagraph b) in 30 ml of methanol with 36 ml of 2N hydrochloric acid and stir overnight. After evaporation of the solvent, an azeotropic mixture is formed between the residue and toluene. 1.56 g of the resulting 1 - [(R) -2-amino-3-hydroxypropyl] -2-indolinone are dissolved in 2 equivalents of an IN sodium hydroxide solution. Add 0.8 g of sodium hydrogen carbonate in 8.1 ml of water and then a solution of 1.46 g of 2-naphthylsulfonyl chloride in 28 ml of dioxane and stir the mixture overnight. . The reaction mixture is poured into 200 ml of a 5% aqueous solution of potassium hydrogensulfate / 10% potassium sulphate and extracted with ethyl acetate. After washing the organic phase with water and drying, the solvent is distilled off. The residue is purified on silica gel using methylene chloride / methanol (98/2) as eluent. 1.9 g of N - [(R) -2-hydroxy-1- (2-oxo-1-indolinylmethyl) -ethyl] -2-naphthyl-sulfonamide are obtained.

d) A solution of 1.82 g of the product prepared in paragraph c) in 70 ml of acetone, at 0 ° C, is treated with 17.4 ml of jones reagent and the mixture is stirred for 4 hours . Pour the reaction mixture over ice and extract with ethyl acetate. After washing the organic phase with water, drying and evaporation, the product is purified on silica gel. using methylene chloride / methanol (19: 1) and 1% acetic acid as eluent. 1.5 g of N- (2-naphthylsulfonyl) -3- (2,3-dioxo-1-indolinyl) -D-alanine are obtained.

e) Using a technique similar to that described in Example 5, from the product prepared in point d), (R) -N - [(RS) -1-amidino-3-piperidinylmethyl] - - acetate is obtained -naftyl-sulfonamido-2,3-dioxo-1-indolinopropionamide (epimers 1: 1). EM-FAB: 671 (M + H) ⁺ .

Example 9

a) To a solution of 7.3 g of (R) -phenylalanine in 120 ml of an IN solution of sodium hydroxide are added 20 g of 2-naphthylsulfonyl rectum in 150 ml of ether. The reaction mixture is stirred for 15 hours and decanted. Separate the aqueous phase, wash with ether, acidify to pH 3 with acid. hydrochloric acid and extract with ethyl acetate. The organic layer is dried and evaporated. The separated crystals are suspended in ether and evaporated by filtration. 14.4 g of

N- (2-naphthyl-sulfonyl) -3-phenyl-D-alanine. P. F .: 146 ° C.

b) The following N-sulfonated amino acids are prepared using a similar process:

N- (2-naphthyl-sulfonyl) -3- (p-chlorophenyl) -D-alanine,

15:4°C.

N- (2-naphthyl-sulfonyl) -3- (p-cyanophenyl) -D-alanine. P.

F.:182°C.

N- (2-naphthyl-sulfonyl) -3- (p-nitrophenyl) -D-alanine. P.

F .: 218 ° C.

N- (2-naphthyl-sulfonyl) -3-benzyl-D-alanine, M.P. 138 ° C. N- (2-naphthylsulfonyl) -D-tryptophan, M.P. 167 ° C.

N- (2-biphenyl-sulfonyl) -D-tryptophan, M.P. 227-230 ° C.

N- (2-antryl-sulfonyl) -D-tryptophan, M.P. 210 ° C.

N- (4-nitrophenyl-sulfonyl) -D-tryptophan, MS: M ⁺ 389 N- (2-nitrophenyl-sulfonyl) -D-tryptophan, PF 70-80 ° C. N- (3-nitrophenyl-sulfonyl) -D-tryptophan, PF: 80-84 ° C. N- (4-benzyloxy-sulfonyl) -D-tryptophan, PF 193 ° C.

N- (3,4-dimethoxyphenyl-sulfonyl) -D-tryptophan, M.P. 182-184 ° C.

34Ν- (2,3,6-trimethyl-4-methoxyphenyl-sulfonyl) -D-tryptophan, EM M ⁺ 416.

N- (2,4,6-triisopropylphenyl-sulfonyl) -D-tryptophan. MS: M ⁺ 470.

N- (2-naphthylsulfonyl) -5-methyl-tryptophan, m.p. 192 ° C.

(R) -2- (2-naphthylsulfonyl) 1,2,3,4-tetrahydro-3-isoquinolinecarboxylic acid, m / e 322, 191, 176, 150, 127.

c) Using a technique similar to that described in Example 5, from the product prepared in point a) the bisulfite of (R) -N - [(RS) -l-amidino-3-piperidinylmethyl] - - ( 2-naphthyl-sulfonamido) -hydrocinamide (epimers 1: 1), EM-FAB: 494 (M + H) ⁺ .

Example 10

a) In 50 ml of dimethylformamide, 1.1 g of a 60% sodium hydride dispersion is suspended. 5.23 g of 4-methyl-3H-1,4,4-benzodiazepine-2,5 (1H, 4H) -dione are added so that the temperature does not exceed 35 ° C and the mixture is stirred for 90 minutes at room temperature. Then a solution of 5.3 g (S) -2,2-dimethyl-4- (£ -tolylsulphonyloxymethyl) -3-oxazolidinecarboxylate t-butyl (Example 6a) in 50 ml of dimethylformamide is added and the mixture is stirred overnight at 50 ° C. The reaction mixture is evaporated and the residue is taken up in ethyl acetate, washed with water and dried. After evaporation of the solvent, the residue is purified on silica gel using ethyl acetate / hexane (1: 1) as eluent. 1.85 g of (R) - (2,3,4,5-tetra-35-hydro-4-methyl-2,5-dioxo-1H-1,4-benzodiazepin-1-yl-methyl are obtained ) T-butyl -2,2-dimethyl-3-oxazolidinecarboxylate.

b) A solution of the product prepared in (a) is treated in 37 ml of methanol with 23 ml of 2N hydrochloric acid. After stirring all night, the reaction mixture is evaporated. 1.37 g of 1 - [(R) -2-amino-3-hydroxypropyl] -3,4-dihydro-4-methyl-2H-1,4-benzodiazepin-2,5 (1H) are dissolved -dione resulting in 15 ml of pyridine and treated with 2.08 g of 2-naphthylsulfonyl chloride. After 3 hours, the reaction mixture is poured into 2N hydrochloric acid and extracted with ethyl acetate. The extracts are washed with water, dried and the solvent is evaporated. The residue is purified on silica gel using methylene chloride / methanol (97: 3) as eluent. 0.5 g of N - [(R) -l-hydroxymethyl-2- (2,3,4,5-tetrahydro-4-methyl-2,5-dioxo-1H-1,4,4) benzodiazepin-1-ylmethyl) -ethyl] -2-naphthyl-sulfonamide.

(c) at 0 ° C, a solution of 0.4 g of the product prepared in (b) in 12 ml of acetone is treated with 3 ml of Jones reagent. After 3 hours, pour the reaction mixture, at room temperature, onto ice and extract with ethyl acetate. After washing with water and drying, after evaporation, 0.4 g of N- (2-naphthylsulfonyl) -3- (2,3,4,5-tetrahydro-4-methyl-2) are obtained, 5-dioxo-1H-1,4-benzodiazepin-1-yl) -D-alanine.

d) Using a technique similar to that described in Example 5, from the product prepared in point c), (R) -N- [(RS) -l-amidino-3-piperidinylmethyl] -1,2,3 is obtained , 4-tetrahydro-2-methyl- - (2-naphthyl-sulfonamide) -1,4-dioxo-5H-2,5-benzodiazepin-5-propionamide (epimers 1: 1), EM-FAB: 606 ( M + H) +

Example 11

a) A solution of 1.25 g of 6-acetoxynaphthyl-2-sulfonyl chloride is added dropwise [Monatsh. 49 (1928) 96] in 4.4 ml of acetone, to a solution of 0.9 g of D-tryptophan in 4.8 ml of IN sodium hydroxide and 4.8 ml of acetone and the pH remains the same to 9 by adding IN sodium hydroxide. The acetone is then evaporated, the resulting suspension is acidified with 1N hydrochloric acid and the product is extracted with ethyl acetate. The product is chromatographed on silica gel using ethyl acetate / acetone (1: 1) as eluent. The main fraction is treated with 8.8 ml of a 0.5 N sodium hydroxide methanolic solution and stirred for 17 hours. The solution is evaporated, treated with water and 1N hydrochloric acid and extracted with ethyl acetate. Purification on silica gel with a mixture of ethyl acetate / acetone (3: 2) gives 0.54 g of N- (6-hydroxy-2-naphthylsulfonyl) -D-tryptophan.

MS: M ⁺ 410, m / e 207, 130.

b) Using a technique similar to that described in Example 5, the (R) -N - [(RS) -1-amidine-3-piperidinylmethyl] - - () hydrochloride is obtained. 6-hydroxy-2-naphthyl-sulfonamido) -indol-3-propionamide (epimers 1: 1), EM-FAB: 549 (M + H) ⁺ .

Example 12

The following compounds are prepared using techniques similar to those described in Examples 5 and 9:

a) (R) -N - [(RS) -1-amidino-3-piperidinylmethyl] - β-fluoro-0 ^ - (2-naphthyl-sulfonamido) -hydrocinamamide bisulfite (epimers 1: 1). EM-FAB: 512 (M + H) ⁺ .

b) (R) -N - [(RS) -1-amidino-3-piperidinylmethyl] bis-chloro- (2-naphthylsulfonamido) -hydrocinamamide bisulfite (epimers 1: 1). EM-FAB: 528 (M + H) ⁺ .

c) (R) -N - [(RS) -1-amidino-3-piperidinylmethyl] -? -cyano-0 ^ - (2-naphthylsulfonamido) -hydrocinamamide bisulfite (epimers 1: 1). EM-FAB: 519 (M + H) ⁺ .

d) (R) -N - [(RS) -1-amidino-3-piperidinylmethyl] - - (2-naphthylsulfonamido) - β-nitrohydrocinamamide bisulfite (epimers 1: 1). EM-FAB: 539 (M + H) ⁺ .

e) (R) -p-Amino-N - [(RS) -1-amidino-3-piperidinylmethyl] ~ θ bisulfite (~ (2-naphthyl-sulfonamido) -hydrocinamamide (epimers 1: 1). 509 (M + H) ⁺ .

f) (R) -N - [(RS) -1-amidino-3-piperidinylmethyl] -3- (johydroxyphenyl) -2- (2-naphthylsulfonamido) -propionamide bisulfite (epimers 1: 1). EM-FAB: 510 (M + H) ⁺ .

Example 13

The following compounds are prepared using techniques similar to those described in Examples 5 to 9:

a) (R) -N - [(RS) -1-amidino-3-piperidinylmethyl] - - (2-naphthylsulfonamido) -o-nitrohydrocinamamide bisulfite (epimers 1: 1). EM-FAB: 539 (M + H) ⁺ .

b) (R) -N - [(RS) -1-amidino-3-piperidinylmethyl] - - (2-naphthylsulfonamido) -cyclohexapropionamide bisulfite (epimers 1: 1). EM-FAB: 500 (M + H) ⁺ .

c) (R) -N - [(RS) -1-amidino-3-piperidinylmethyl] -2- (2-naphthylsulfonamido) -4-phenylbutyramide bisulfite (epimers 1: 1). EM-FAB: 508 (M + H) ⁺ .

d) (R) -N - [(RS) -1-amidino-3-piperidinylmethyl] - - (2-naphthyl-sulfonamido) -cyclohexanobutyramide bisulfite (epimers 1: 1). EM-FAB: 514 (M + H) ⁺ .

e) (R) -N - [(RS) -1-amidino-3-piperidinylmethyl] - - (2-naphthyl-sulfonamido) -1-naphthyl-propionamide bisulfite. EM-FAB: 586 (M + H) ⁺ .

f) (R) -N - [(RS) -1-amidino-3-piperidinylmethyl] - (2-naphthyl-sulfonamido) -2-naphthyl-propionamide bisulfite (epimers

1: 1). EM-FAB: 544 (M + H) ⁺ .

g) (R, 2S, 4aR and / or S, 8aR and / or S) bisulfite -N - [(RS) -1-amidino-3-piperidinylmethyl] -decahydro- (- (2-naphthyl- sulfo namido) -2-naphthyl-propionamide (mixture of diastereomers) EM-FAB: 544 (M + H) ⁺ .

h) (R) -N - [(RS) -1-amidino-3-piperidinylmethyl] - - (2-naphthyl-sulfonamido) -4-imidazole-propionamide bisulfite (epimers 1: 1). EM-FAB: 484 (M + H) ⁺ .

i) (R) -N - [(RS) -1-amidino-3-piperidinylmethyl] - - (2-naphthylsulfonamido) -2-thienyl-propionamide bisulfite (epimers 1: 1). EM-FAB: 500 (M + H) ⁺ .

-39Example 14

The following compounds are prepared using techniques similar to those described in Examples 5 and 11:

a) (R) -N - [(RS) -1-amidino-3-piperidinylmethyl] - 0 ^ - (3-methyl-8-quinoline-sulfonamido) -indol-3-propionamide bisulfite (epimers 1: 1) . EM-FAB: 548 (M + H) ⁺ .

b) (R) -N - [(RS) -1-amidino-3-piperidinylmethyl] - - [(RS) -3-methyl-1,2,3,4-tetrahydro-8-quinoline-bisulfite ] -indole-3-propionamide sulfonami (epimers 1: 1). MS-FAB: 552 (M + H) ⁺ .

c) (R) -N - [(RS) -1-amidino-3-piperidinylmethyl] - - (4-biphenyl-sulfonamido) -indol-3-propionamide hydrochloride (epimers 1: 1). EM-FAB: 559 (M + H) ⁺ .

d) (R) -N - [(RS) -1-amidino-3-piperidinylmethyl] - - (2-anthryl-sulfonamido) -indol-3-propionamide hydrochloride (epimers 1: 1). EM-FAB: 583 (M + H) ⁺ .

e) (R) -N - [(RS) -1-amidino-3-piperidinylmethyl] - - [5- (1-methyl-5-trifluoromethyl-pyrazol-3-yl) -2-thienyl-sulfo bisulfite ] -indol-3-propionamide (epimers 1: 1). EMFAB: 637 (M + H) ⁺ .

f) (R) -N - [(RS) -1-amidino-3-piperidinylmethyl] - (£ -iodo-benzenesulfonamido) -indol-3-propionamide hydrochloride (epimers 1: 1). EM-FAB: 609 (M + H) ⁺ .

g) (R) -N - [(RS) -1-amidino-3-piperidinylmethyl] ~ ύ (-o ^- iodobenzenesulfonamido) -indol-3-propionamide hydrochloride (epimers 1: 1). EM-FAB: 608 (M + H) +

h) (R) -N - [(RS) -1-amidino-3-piperidinylmethyl] -D (~ [£ -nitro-benzenesulfonamido) -indol-3-propionamide hydrochloride (ep. 1: 1). EM-FAB: 528 (M + H) ⁺ .

i) (R) -N - [(RS) -1-amidino-3-piperidinylmethyl] - - (o-nitro-benzenesulfonamido) -indol-3-propionamide hydrochloride (epj. mere 1: 1). EM-FAB: 528 (M + H) ⁺ .

j) (R) -N - [(RS) -1-amidino-3-piperidinylmethyl] - - (m-nitro-benzenesulfonamido) -indol-3-propionamide hydrochloride (epimers 1: 1). EM-FAB: 528 (M + H) ⁺ .

k) (R) -N - [(RS) -1-amidino-3-piperidinylmethyl] - - (£ -benzyloxy-benzenesulfonamido) -indol-3-propionamide hydrochloride (epimers 1: 1). EM-FAB: 589 (M + H) ⁺ .

l) (R) -N - [(RS) -1-amidino-3-piperidinylmethyl] - θ (- (3/4-dimethoxy-benzenesulfonamido) -indol-3-propionamide hydrochloride (epimers 1: 1). -FAB: 543 (M + H) ⁺ .

m) (R) -N - [(RS) -1-amidino-3-piperidinylmethyl] “$ - (4-methoxy-2,3,6-trimethyl-benzenesulfonamido) -indol-3-propionamide hydrochloride (epimers 1 :1). EM-FAB: 555 (M + H) ⁺ .

n) (R) -N - [(RS) -1-amidino-3-piperidinylmethyl] -2,4,6-triisopropyl-benzenesulfonamido) -indole-3-propion hydrochloride (1: 1 epimers). EM-FAB: 609 (M + H) ⁺ .

Example 15

The following compounds are prepared using a technique similar to that described in Example 5:

41a) (RS) -N - [(RS) -1-amidino-3-piperidinylmethyl] -5-methyl- ¢ (- (2-naphthylsulfonamido) -indol-3-propionamide bisulfite. EM-FAB: 547 (M + H) ⁺ .

b) (RS) -N - [(RS) -1-amidino-3-piperidinylmethyl] -5-fluoro- - (2-naphthyl-sulfonamido) -indol-3-propionamide bisulfite. EM-FAB: 551 (M + H) ⁺ .

c) 3 - [(R) -2 - [(RS) -1-amidino-3-piperidinyl-methylcarbamoyl] -2- (2-naphthyl-sulfonamido) -ethyl] -indol-1-acetic bisulfite (epimers 1: 1). EM-FAB: 591 (M + H) ⁺ .

Example 16

Using techniques similar to those described in Examples 6 and 7, we obtain, respectively:

a) (R) -N - [(R) -1-amidino-3-piperidinylmethyl] bisulfite - 0 (- (2-naphthylsulfonamido) -indol-3-propionamide. E.M.-FAB:

533 (M + H) ⁺ , and

b) N- (2-naphthylsulfonyl) -D-tryptophan ester (R) -1-amidino-3-piperidinylmethyl (1: 1). EM-FAB: 534 (M + H) ⁺ .

Example 17

The following compounds are obtained using techniques similar to those described in Examples 6 and 7:

-44d) (R) -N- [(RS) -1-amidino-3-piperidinylmethyl] -3,4-hydro- (2-naphthylsulfonamido) - oxo-2 (1H) -isoquinolinobutyramide (epimers 1: 1). EM-FAB: 577 (M + H) ⁺ .

e) (RS) -N - [(RS) -1-amidino-3-piperidinylmethyl] -2- (2-naphthyl-sulfonamido) -3- (o-nitrobenzoyl) -propionamide bisulfite. EM-FAB: 567 (M + H) ⁺ .

f) (R) -N - [(RS) -1-amidino-3-piperidinylmethyl] -3- (o-amino-benzoyl) -2- (naphthyl-sulfonamido) -propionamide (epimers 1: 1). EM-FAB: 537 (M + H) ⁺ .

g) (R) -N - [(RS) -1-amidino-3-piperidinylmethyl] 3-anthraniloyl-2- (? -iodobenzene-sulfonamido) -propionami trifluoroacetate (epimers 1: 1). EM-FAB: 613 (M + H) ⁺ .

h) (R) -N - [(RS) -1-amidino-3-piperidinylmethyl]] - 3- (o-formamidobenzoyl) - | / - (2-naphthylsulfonamido) -propionamide acetate (epimers 1: 1 ). EM-FAB: 565 (M + H) ⁺ .

Example 19

a) 164 ml of a 70% sodium hydroxide solution are added with 199 g of 2-aminoethyl hydrogensulfate, the resulting solution is heated to 50 ° C and added dropwise to a solution of (RS) -benzyloxymethyloxirane in 280 ml of methanol. After 1 hour at 50 ° C, an additional 280 ml of 70% sodium hydroxide solution is added and the solution is stirred overnight. The reaction mixture is then poured onto ice and extracted with toluene. Wash the organic phase with water, dry and evaporate. After distillation, 26.8 g of racemic 2-benzyloxythyl-morpholine are obtained. MS: M ⁺ -91 = 116 (benzyl).

b) To a solution of 31.0 g of di-t-butyl dicarbonate in 287 ml of dioxane is added 26.8 g of the product prepared in (a) in 287 ml of dioxane and the reaction mixture is stirred for all night. After evaporation of the solvent and chromatography of the residue on silica gel using ethyl acetate / hexane as eluent, 15 g of racemic t-butyl 2-benzyloxymethyl-morpholinecarboxylate are obtained. MS: M ⁺ -56 = 251 (isobutylene).

c) In the presence of 1.5 g of palladium on coal and under normal conditions, a solution of 15 g of the product prepared in paragraph b) in 300 ml of ethanol is hydrogenated and, after filtration and evaporation of the solvent, it is obtained quantitatively o racemic t-butyl 2-hydroxymethyl-4-morpholinecarboxylate. MS: M ⁺ = 217.

d) It is a solution of 8.8 g of the product prepared there. nea c) in 44 ml of pyridine with 9.4 g of p-chlorobenzenesulfonyl chloride. After stirring for 5 hours, the reaction mixture is evaporated, the residue is taken up in ethyl acetate and washed with a 10% copper sulphate solution. After drying the organic phase, evaporating the solvent and chromatography of the residue on silica gel using ethyl acetate / hexane as eluent, 14.7 g of racemic 2- (--chloro-phenylsulfonyloxymethyl) -4-morpholinocarboxylate are obtained t-butyl. MS: 392 (M + H) ⁺ .

c) A solution of 14.7 g of the product prepared in

Λ.

d) in 91 ml of dimethylformamide 7.3 g of sodium azide are added. After stirring for 24 hours at 50 ° C, the reaction mixture is poured onto ice and extracted with ether. The organic phase is washed with water, dried and evaporated. 8.1 g of racemic t-butyl 2-azidomethyl-4-morpholinocarboxylate are obtained.

f) In the presence of 0.8 g of platinum oxide, a solution of 8.1 g of the product prepared in line e) in 92 ml of ethanol is hydrogenated for 4 hours under normal conditions, isolating 6.5 g of racemic t-butyl 2-aminomethyl-4-morpholinocarboxylate. MS: (M + H) ⁺ -56 = 159 (isobutylene).

g) Treat a solution of 3.4 g of N- (2-naphthylsulfonyl) -D-tryptophan (Example 9) in 35 ml of dimethylformamide with 1.2 ml of 4-ethyl-morpholine and with 3, 4 g benzotriazol-1-yloxy-tris (dimethylamino) -phosphonium hexafluorophosphate. A solution of 2.0 g of the product prepared in subparagraph (f) in 2 ml of dimethylformamide is added and the solution is stirred overnight. The solvent is then distilled off and the residue is taken up in ethyl acetate and washed with water.

After drying, solvent evaporation and chromatography of the residue on silica gel using ethyl acetate as the eluent, 4.5 g (RS) -2-N- (2-naphthylsulfonyl) -D-tryptophylaminomethyl-4 are obtained racemic t-butyl morpholinocarboxylate.

MS: (M + H) ⁺ -56 = 537 (isobutylene).

h) Treat a solution of 2 g of the product prepared in point g) in 20 ml of ethyl acetate with 20 ml of a 4 molar solution of hydrochloric acid in ethyl acetate. After stirring, the solution is evaporated to dryness. The residue dissolves

in 20 ml of dimethylformamide, treat with 1.4 ml of triethyl amine and 0.5 g of formamidinesulfonic acid and stir for 17 hours at room temperature. The solvent is then evaporated, the residue is taken up with 50 ml of ethyl acetate and 10 ml of methanol and the solution is washed with water. After drying the organic phase, evaporating the solvent and chromatography of the residue on an RP column (alkyl silica gel) using water / acetonitrile as eluent, 0.1 g of (R) -N- (RS) is obtained. -4-amidino-2-morpholinomethyl] - (Á - (2-naphthylsulfonamido) -indol-3-propionamide. MS: 535 (M + H) ⁺ .

Example 20

Using techniques similar to those described in Example 19 g) and h), from the racemic t-butyl 2-hydroxymethyl-4-morpholinocarboxylate (Example 19 c) and N- (2-naphthyl-sulphonyl) -D-tryptophan, N- (2-naphthyl-sulfonyl) -D-tryptophan no. (RS) -4-amidino-2-morpholinylmethyl bisulfite is obtained. E.M .: 536 (M + H).

Example 21

Using a technique similar to that described in Example 19, we obtain:

a) (R) -N- (RS) -4-amidino-2-morpholinylmethyl] - Pf - (2-naphthylsulfonyl) - £ -nitrohydrocinamamide bisulfite. MS: 541 (M + H) ⁺ ;

b) (R) -N- [(RS) -4-amidino-2-itiorfolinylmethyl] ->> - (2-naphthylsulfonamido) -2-thienyl-propionamide bisulfite. MS: 502 (M + H) ⁺ ;

c) (R) -N - [(RS) -4-amidino-2-morpholinylmethyl] -3- (o-aminobenzoyl) -2- (2-naphthyl-sulfonamido) -propionamide bisulfite. MS: 539 (M + H) ⁺ .

Example 22

a) Treat a solution of 10 g of (D) -phenylalanine benzyl ester β-toluenesulfonate in 150 ml of methylene chloride with 8.2 ml of triethylamine and cool to 0 ° C 5.8 g of 2-naphthylsulfonyl chloride are added and the mixture is stirred for 12 hours at room temperature. The reaction mixture is evaporated, the residue is taken up with 200 ml of ethyl acetate, the precipitated triethylammonium chloride is filtered off with suction and the mother solution is washed with water. After evaporation of the organic phase and crystallization from hexane, 9.7 g of the N- (2-naphthyl-sulfonyl) -3-phenyl-D-alanine benzyl ester are obtained. P. F. 107 ° C.

b) This is a 3g solution of the product prepared in

a) in 40 ml of tetrahydrofuran, at -80 ° C, with ml of 1.6 M butyl lithium in hexane and then 1.2 ml of t-butyl bromoacetate. After stirring for 2 hours at room temperature, the reaction mixture is taken up with 200 ml of ethyl, washed with water and the organic phase is evaporated. The product is purified on silica gel using hexane / ethyl acetate (9: 1) as eluent. 1.35 g of the benzi ester are obtained

, .- 49 N- (t-butyloxycarbonylmethyl) -N- (2-naphthylsulfonyl) -3-phenyl-D-alanine cyclic. NMR (CDCl ₃ ) 1.45 (s, 9H, t-butyl).

c) In the presence of 0.3 g of palladium on coal, a solution of 1.35 g of the product prepared in (b) in 50 ml of ethanol is hydrogenated. After evaporation of the reaction mixture and formation of an azeotropic mixture with toluene, 0.95 g of N- (t-butoxycarbonylmethyl) -N- (2-naphthyl-sulfonyl) -3-phenyl-D-alanine is obtained.

d) Using a technique similar to that described in Example 5, N - [(R) - 0 ^ - [[(S) -1-amidino-3-piperidinyl] -methyl-car bamoyl] -phenethyl] - is obtained N- (2-naphthylsulfonyl) -glycine. EM-FAB: 552 (M + H) ⁺ .

Example 23

a) To a solution of 10.0 g of β-benzyl ester of N-Boc-L-aspartic acid with 200 ml of dimethylformamide is added 13.7 g of benzotriazol-yloxy-tris (dimethylamino) phosphonium hexafluorophosphate and 16 , 9 ml of benzylamine and the reaction mixture is stirred overnight at room temperature. The solvent is then evaporated and the residue is taken up in ethyl acetate and washed with water. After drying, evaporation and chromatography on silica gel using ethyl acetate / hexane (1: 4) as eluent, 5.4 g of (S) -3- (1,1-di-methoxycarbonylamino) -4- benzyl benzylamino-4-oxo-butyrate.

b) A solution of 2.0 g of the product prepared in (a) in 10 ml of ethyl acetate is treated with 10 ml of a 4 molar solution of hydrochloric acid with ethyl acetate. After stirring for 3 hours, the mixture is evaporated and the residue is suspended in 30 ml of dioxane. Add 5 ml of a solution of IN sodium hydroxide, 0.8 g of sodium hydrogen carbonate, 20 ml of water and then a solution of 1.1 g of 2-naphthylsulfonyl chloride in 15 ml of dioxane and the mixture is stirred overnight at room temperature. The reaction mixture is poured into a 5% potassium hydrogen sulfate / 10% potassium sulfate solution and extracted with ethyl acetate. After drying and evaporating the organic phase, the residue is recrystallized from a mixture of ethyl acetate / hexane. 1.8 g of (S) -2-benzyl-carbamoyl-N- (2-naphthylsulfonyl) -alanine benzyl ester are obtained.

c) Treat a solution of 1.0 g of the product prepared in (b) in 20 ml of methanol with 2 ml of a solution of 1N sodium hydroxide and stir overnight at room temperature. The mixture is acidified, extracted with ethyl acetate and, after evaporation, the residue obtained is crystallized from a mixture of methanol / methylene chloride / hexane. 0.3 g of (S) -2-benzylcarbamoyl-N- (2-naphthylsulfonyl) -pht-alanine are obtained.

d) Using a technique similar to that described in Example 5, the (S) -N- [(RS) -1-amidino-3-piperi-dinylmethyl] -3-benzyl-carbamoyl-3- (2) trifluoroacetate is obtained -naphthyl-sulfonamido) -propionamide (epimers 1: 1), EM-FAB: 551 (M + H) ⁺ .

Example 24

Using a technique similar to that described in Example &

*

23, via (R) -2-benzyl-carbamoyl-N- (2-naphthyl-sulfonyl) - β -alanine, (R) -N- (RS) -l-amidino-3- hydrochloride is obtained peridinylmethyl] -3-benzyl-carbamoyl-3- (2-naphthyl-sulfonamide. EM-FAB: 551 (M + H) ⁺ .

Example 25

Using a technique similar to that described in example 23 and using hexamethylenimine instead of benzylamine, (S) -N - [(RS) -l-amidino-3-piperidinylmethyl] -hexa-hydro- β - ( 2-naphthyl-sulfonamido) -% -οχο-ΙΗ-1-azep ^ nabutiramide. EM-FAB: 543 (M + H) ⁺ .

Example 26

Using a technique similar to that described in Example 6, (R) -N - [(S) -l-amidino-3-piperadinyl methyl] -1,2,3,4-tetrahydro-2 hydrochloride is obtained - (2-naphthylsulfonyl) -3-isoquinoli. nacarboxamide. EM-FAB: 506 (M + H) ⁺ .

Example 27

Using techniques similar to those described in Examples 5 and 9, methyl o- (R) - tf - [(RS) -1-amidino-3-piperidinylmethylcarbamoyl] -p-nitrophenethyl-sulfamoyl] -benzoate is obtained. MS: FAB: 547 (M + H) ⁺ .

Example 28

Using techniques similar to those described in Examples 5 and 9, (RS) -N - [[(RS) -1-amidino-3-piperidinyl] -methyl] -5-bromo--2 is obtained -naftil-sulfonamidoindol-3-propionamide. EM-FAB: 611 (M + H) ⁺ .

Example 29

The following compounds are prepared using techniques similar to those described in Examples 6 and 9:

a) (R) -N - [[(RS) -1-amidino-3-piperidinyl] -methyl] - £> -iodo- (/ -2-naphthyl-sulfonamido-hydroxinamide £ -toluenesulfonate. EM-FAB: 620 (M + H) ⁺ .

b) (R) -N - [[((S) -1-amidino-3-piperinyl] -methyl] -2 -2-naphthyl-sulfonamido-p-nitrohydrocinamide £ -toluenesulfonate. EM-FAB: 539 (M + H) ⁺ .

Example 30

a) Cool a solution of 30.1 g of t-butyl (R) -4-hydroxymethyl-2,2-dimethyl-3-oxalidinocarboxylate (R) -4-hydroxymethyl ester in 400 ml of methylene chloride to room temperature 0 ° C, and is treated with 27.2 ml of triethylamine. After the addition of 12.1 ml of methanesulfonyl chloride, at 0 ° C, the reaction mixture is stirred for 1 hour. The salts are filtered off, the filtrate is evaporated and the product is recrystallized from hexane. 32.7 g of t-butyl (S) -2,2-dimethyl-4- (methanesulfonyloxymethyl) -3-oxazolidinecarboxylate are obtained.

¹ H NMR (CDCl ₃ ): 1.48, s, 9H, t-butyl: 3.04, s, 3H, mesyl.

b) A solution of 29.1 g of the product prepared in (a) in 200 ml of dimethylformamide is treated with 24.5 g of sodium azide. The suspension is heated to 50 ° C and stirred for 24 hours. Then the salts are filtered off and the filtrate is evaporated. The crude product is dissolved in 400 ml of ethyl acetate and washed with water. The organic phase is dried and evaporated. 20.2 g of t-butyl (R) -2,2-dimethyl-4- (azidomethyl) -3-oxazolidinecarboxylate are obtained. I.V. (CHCl3) 2140 cm (azide band).

c) Treat a solution of 20.2 g of the product prepared in (b) in 400 ml of dioxane with 4 g of palladium oxide. The reaction mixture is hydrogenated at room temperature and normal pressure. After filtration and evaporation of the filtrate, 17.9 g of t-butyl (R) -2,2-dimethyl-4- (aminomethyl) -3-oxazolidinocarbon xylate are obtained.

d) A solution of the product prepared in paragraph c) is treated in 300 ml of methylene chloride, at 0 ° C, with 19.9 ml of Hunig's base (ethyldiisopropylamine) and 12.2 ml of benzyl chloroformate . After stirring, the reaction mixture is evaporated and the crude product is dissolved in 400 ml of ethyl acetate and washed with 100 ml of water. The organic phase is dried and the impure material is evaporated and purified on silica gel using ethyl acetate / hexane (1: 9) as eluent. 26.4 g of t-butyl (R) -2,2-dimethyl-4- (carbobenzoxiami nomethyl) -3-oxazolidinecarboxylate are obtained.

c) A solution of the product prepared in (c) is treated in 300 ml of methanol with 36.2 ml of 2N hydrochloric acid. After 24 hours, the solution is evaporated and the residue is dissolved in

400 ml of dioxane and treated with 72.43 ml of IN sodium hydroxide. After the addition of 30.4 g of sodium hydrogen carbonate, the suspension is treated with a solution of 24.6 g of 2-naphthylsulfonyl chloride in 100 ml of dioxane. The suspension is stirred for 15 hours, then the reaction mixture is filtered, evaporated, taken up with ethyl acetate, washed with water and dried. The organic phase is evaporated and the crude product is purified on silica gel using ethyl acetate / hexane (3: 7) as eluent. 25.85 g of benzyl [2-naphthyl-sulfoninamido) -propyl] -propyl] -carbamidate are obtained. MS: 415 (M + H) ⁺ , 371 (-CO ₂ ), 347, 325, 281, 269, 225,

191, 135.

f) After adding 1 g of 10% palladium on coal, a solution of 5 g of the product prepared in

e), in 100 ml of ethanol, for 24 hours at room temperature and under normal pressure. The catalyst is filtered off and washed with methanol. After evaporation, 2.8 g of N - [(R) -2-amino-1-hydroxymethyl) -ethyl] -2-naphthyl-sulfonamide are obtained. MS: 281 (M + H) ⁺ 251, 250, 221, 191, 128, 127, 60.

g) A solution of 1.3 g of the product prepared in paragraph f) in 500 ml of dimethylformamide is treated with 0.83 g of phenylglyoxylic acid and 0.9 ml of Hunig's base. After adding 2.0 g of benzotriazol-1-yloxy-tris (dimethyl. Amino) -phosphonium hexafluorophosphate, the reaction mixture is stirred for 5 hours. Evaporate the solvent and purify the crude product on silica gel using hexane / ethyl acetate (1: 1) as eluent. 1.4 g of N - [(R) -3-hydroxy-2- (wet 2-naphthylsulfone) -propyl] -2-phenylglyoxylamide are obtained.

* 55h) at 0 ° C, a solution of 0.42 g of the product prepared in paragraph g) in 30 ml of acetone is treated with 3.5 ml of Jones' reagent (2.67 m'g of chromium in sulfuric acid). The mixture is stirred for 1 hour, poured over a mixture of water and ice and extracted with ethyl acetate. it. The organic phase is dried and evaporated. 0.44 g of (R) -2- (2-naphthylsulfonamido) -3- (2-phenyl-glyoxylamido) -propionic acid is obtained. MS-FAB: 427 (M + H) ^.

i) Using a technique similar to that described in Example 5, from the product prepared in point h) the £ -tol our sulfonate fr (R) -N - [[(S) -l-amidino-3-piperidinyl] is obtained -methyl] -2-naphthyl-sulfonamido-3- (2-phenyl-glyoxylamido) -propionamide. EM-FAB: 565 (M + H) ⁺ .

Example 31

Using techniques similar to those described in Examples 6 and 9, we obtain:

a) via N - [(6-benzyloxy-2-naphthyl) -sulfonyl] -D-tryptophan,

EM-FAB: 394 (M + H) ⁺ , (R) -N - [[(RS) -1-amidino-3-piperidinyl] -methyl] - - (6-benzyloxy-2-naphthyl-sulfonamido hydrochloride ) -indol-3-propionamide. EM-FAB: 639 (M ⁺ ).

b) via N- (1-naphthyl-sulfonyl) -D-tryptophan. EM-FAB: 394 (M + H) ⁺ , (R) -N - [[(RS) -1-amidino-3-piperidinyl] -methyl] - - (1-naphthyl-sulfonamido) -indol- hydrochloride 3-propionamide. EM-FAB: 533 (M + H) ⁺ ,

c) via N- (2-naphthyl-sulfonyl) -3- (m-nitrophenyl) -DL-alanine,

-56ς

Ε.Μ .: 400 (Μ), ο (RS) -Ν - [[((RS) -l-amidino-3-piperidinyl] -methyl] hydrochloride - - (2-naphthyl-sulfonamido) -m-nitro- hydrocinamamide. EM-FAB: 539 (M + H) ⁺ .

Example 32

a) To a solution of 0.71 g of D-tryptophan in 4.8 ml of water and 3.12 ml of IN sodium hydroxide are added 0.36 g of sodium hydrogen carbonate and a solution of 0.50 g of methyl p- (chlorosulfonyl) -benzoate in 10 ml of ether. The resulting suspension is stirred for 22 hours. The sodium salt is separated from N - [[p- (methoxycarbonyl) phenyl] -sulfonyl] -D-tryptophan by suction filtration and washed with water (0.52 g). AND.

M .: 400 (M-Na). After acidification with nitric acid, 0.38 g of the product is separated from the stock solution in the form of free acid.

b) Using techniques similar to those described in Examples 5 and 11, from the acid prepared in point a), p - [[(R) -1 - [[[(RS) -l-amidino-3 -piperidinyl] -methyl] -carbamoyl] -2-indol-3-ylethyl] -benzoate. EM-FAB: 541 (M + H) ⁺ .

Example 33

By a similar technique described in Example 31, (RS) -N - [[(S) -1-amidino-3-piperidinyl] -methyl--2-naphthyl-sulfonamido-m-nitro-hydrocinamamido hydrochloride is obtained . EM-FAB: 539 (M + H) ⁺ .

Example 34

It is a solution of 0.15 g of (RS) - -N - [[((S) -1-amidino-3-piperidinyl] -methyl] - -2-naphthyl-sulfone mido-m-nitro- hydrocinamamide (Example 33) in 50 ml of ethanol with 0.12 g of 10% palladium on charcoal and hydrogenates at room temperature and under normal pressure. The reaction solution is filtered and evaporated, the residue is dissolved in methanol and treated with ether. By suction filtration, the (RS) -N - [[((S) -1-amidino-3-piperidinyl] -methyl] -m-amino--2-naphthyl-sulfonamido-hydrocinamamide hydrochloride is separated and washed with ether. 0.12 g is obtained. EM-FAB: 509 (M + H) ⁺ .

Example 35

a) A solution of 50 g of N- (2-naphthylsulfonyl) -3- (£ -nitrophenyl) -D-alanine (Example 9B) in 100 ml of dimethyl formamide is treated with 45 ml of Raney nickel and hydrogenates at room temperature and under normal pressure. The reaction solution is filtered and then concentrated and poured into water. Using suction filtration, separate 3- (£ -aminophenyl) -N- (2-naphthylsulfonyl) -D-alanine, wash with water and dry. Yield 37.6 g. PF 211 ° -212 ° CEM 370 (M) ⁺ .

b) A suspension of 1.0 g of the product prepared in (a) in 15 ml of methylene chloride is treated with 1.13 ml of triethylamine. The resulting solution is cooled in an ice bath and treated with a solution of 0.3 ml of monoethyloxalyl chloride in 5 ml of methylene chloride. After more minutes in the ice bath, the solution is stirred throughout

at night at room temperature. The reaction mixture is concentrated, the residue is dissolved in water and acidified with water. 10% citric acid and the product is separated by suction filtration. Dissolve in ethyl acetate, wash with water and dry. After evaporation, 0.92 g of the amide of the oxalic acid ester is obtained which, in a manner analogous to that described in Example 5, gives 0.87 g of 4 '- [(R) -2 - [[[( RS) Ethyl -1-amidino-3-piperidinyl] -carbamoyl] -2 - [(2-naphthylsulfonamido) -ethyl] -oxa nilate. EM-FAB: 609 (M + H) ⁺ .

Example 36

The following compounds are prepared using techniques similar to those described in Example 35:

a) 4 '- [(R) - [[[((RS) -l-amino-3-piperidinyl] -methyl] -carbamoyl] -2 - [(2-naphthyl-sulfonamido) -ethyl] -succinanylate hydrochloride methyl. EM-FAB: 623 (M + H) ⁺ .

b) 3 ¹ - [(RS) -2 - [[[((RS) -1-amidino-3-piperidinyl] -methyl] -carbamoyl] -2 - [(2-naphthyl-sulfonamido) -ethyl] - hydrochloride methyl succinanylate. EM-FAB: 623 (M + H) ⁺ .

c) 4 '- [(R) -2 - [[[((RS) -l-amidino-3-piperidinyl] -methyl] -carbamoyl] -2 - [(2-naphthyl-sulfonamido) -ethyl] - hydrochloride - benzyl succinanylate. EM-FAB: 699 (M + H) ⁺ .

d) 4 '- [(R) -2 - [[[((RS) -1-amidino-3-piperidinyl] -methyl] -carbamoyl] -2 - [(£ -iodobenzenesulfonamido) -ethyl] -sucine hydrochloride methyl. EM-FAB: 699 (M + H) ⁺ ,

e) 4 '- [(R) -2 - [[[((RS) -1-amidino-3-piperidinyl] 9-methyl] -carbamoyl] -2 - [(2-naphthyl-sulfonamido) -ethyl] hydrochloride] - ethyl carbanyl. EM-FAB: 581 (M + H) ⁺ .

Example 37

Using a technique similar to that described in Example 35, N- (2-naphthylsulfonyl) -3- [jo- (2-phenyl-glyoxylamido) -phenyl] -D-alanine [EM: 502 (M ⁺ )] in which it is converted in a similar manner to that described in Example 6 (e) to g) to (R) -N - [[(S) -1-amidino-3-piperidinyl] -methyl- o hydrochloride (- ( 2-naphthylsulfonyl) - £ - (2-phenyl-glyoxylamino) -hydrocinamamide EM-FAB: 641 (M + H) ⁺ .

Example 38

Using techniques similar to those described in Examples 35 and 42, via £ - [p - [(R) -2 - [[(RS) -1-amidino-3-piperidinyl] -methyl] -carbamoyl] -2- hydrochloride (2-naphthyl-sulfonamido) -ethyl] -benzamido] -methyl benzoate [EM-FAB: 671 (M + H) ⁺ ], acid hydrochloride £ - [£ - [(R) -2- [[[(RS) -1-amidino-3-piperidinyl] -methyl] -carbamoyl] -2- (2-naphthylsulfonamido) -ethyl] -benzami do] -benzoic. EM-FAB: 657 (M + H) ⁺ .

Example 39

In an analogous manner to that described in Example 35, (R) -N - [[(RS) -1-amidino-3-piperidinyl] methyl]] - £ - [2- (2-methoxyethoxy) hydrochloride is obtained ) -acetamido] - tf -2-naphthyl-sulfonamido-hydrocinamamide. EM-FAB: 625 (M + H) ⁺ .

-60,

Example 40

In an analogous manner to that described in example 35, 4 ¹ - [(R) -2 - [[[((S) -1-amidino-3-piperidinyl] -methyl] -carbamoyl] -2 hydrochloride is obtained - (2-naphthyl-sulfonamido) -ethyl] -oxanil. EM-FAB: 581 (M + H) ⁺ .

Example 41

A solution of 0.7 g of 3- (p-aminophenyl) -N- (2-naphthylsulfonyl) -D-alanine (Example 35 a)) in 5 ml of pi is treated. ridina with 1 ml of acetic anhydride and left to stand for 20 hours at room temperature. After adding water and concentrated hydrochloric acid (cooling with ice), the product is separated by suction filtration, dissolved in ethyl acetate, washed with water, dried and evaporated. The resulting product is dissolved in 20 ml of 1N methanolic sodium hydroxide solution and left to stand. Eva, the solution is poured, the residue is dissolved in water, acidified with concentrated hydrochloric acid, the precipitated product is separated by suction filtration, dissolved in ethyl acetate and washed with water. After evaporation, the residue is reacted in a manner analogous to that described in Example 5, obtaining 146 mg of hydrochloride dè (R) -p-acetamido-N - [[(RS) -l-amidino-3- piperidinyl] -methyl- - (2-naphthylsulfonamido) -hydrocinamamide. EM-FAB. 551 (M + H) ⁺ .

Example 42

At room temperature a mixture dissolves with agitation

Q * 4 mg suspension of 4 '- [(R) -2 - [[[(RS) -1-amino-3-piperidinyl] -methyl] -carbamoyl] -2- (2-naphthyl-sulfonamido) suspension ) Ethyl] -ethyl] -oxanilate (Example 35) in 10 ml of an 0.1N ethanolic solution of sodium hydroxide. The reaction solution is acidified with a 2.78N ethanolic hydrochloric acid solution, the sodium hydrochloride is separated by suction filtration and the filtrate is treated with ether. The resulting hydrochloride is decanted off and stirred with ether. By suction filtration, the resulting product is separated. Yield, however: 60 mg of 4 '- [(R) -2 - [[[((RS) -1-amino dino-3-piperidinyl] -methyl] -carbamoyl] -2- (2-naphthyl) hydrochloride -sulfonamido) -ethyl] -oxanil. EM-FAB: 581 (M + H) ⁺ .

Example 43

This is a solution of 0.5 g of 4 '- [(R) -2 - [[[((RS) -l-amidino-3-piperidinyl] -methyl] -carbamoyl] -2- (2- benzyl naphthylsulfonamido) -ethyl] -succinanilate (Example 36 c) in 20 ml of ethanol with 0.5 g of 10% palladium on charcoal and hydrogenates. Separate the catalyst by filtration, concentrate the filtrate and treat the residue with ether. By decanting, the resulting product is separated, stirred with ether and finally separated by suction filtration. Yield: 0.35 g of 4 ¹ - [(R) -2 - [[[((RS) -1-amidino-3-piperidinyl] -methyl] -carbamoyl] -2- (2-naphthyl- wet sulfone) -ethyl] -succinanilide. EM-FAB: 609 (M + H) ⁺ .

Example 44

This is a 0.5 g solution of 3- (jo-aminophenyl) -N-

-62- (2-naphthylsulfonyl) -D-alanine (Example 35 a) in 1.35 ml of IN sodium hydroxide and 7 ml of water with 6 ml of dioxane and 0.34 g of sodium hydrogen carbonate. With stirring, 0.26 g of tosyl chloride is added. After stirring for 24 hours at room temperature, the solution is concentrated, diluted with water and extracted with ether. The aqueous phase is treated with 6 ml of 2N hydrochloric acid while cooling with ice and the resulting product is separated by suction filtration. In a manner analogous to that described in Example 5, this product is converted without purification to 0.39 g of (R) -N - [[(RS) -1-amidino-3-piperidinyl] -methyl] - hydrochloride -2-naphthyl-sulfone mido- (p-toluenesulfonamido) -hydrocinamamide. EM-FAB: 663 (M + H) ⁺ .

Example 45

In an analogous manner to that described in Example 44, (R) -N - [[((S) -1-amidino-3-piperidinyl] -methyl] - £ - (£ -iodobenzenesulfonamido) - - ( 2-naphthyl-sulfonamido) -hydrocinamamide. EM-FAB: 775 (M + H) ⁺ .

Example 46

In a manner analogous to that described in Example 44, via £ - [[£ - [(R) -2 - [[[(RS) -1-amidino-3-piperidinyl] -methyl] -carbamoyl] -2 hydrochloride - Methyl (2-naphthyl-sulfonamido) -ethyl] -phenyl] -sul ^ famoyl] -benzoate (EM-FAB: 707 (M + H) ⁺ ], the acid hydrochloride £ - [[£ - [(R) -2 - [[[((RS) -1-amidino-3-piperidinyl] -methyl] -carbamoyl-2- (2-naphthyl-sulfonamido) -ethyl] -phenyl] -sulfamoyl] -benzoic -FAB: 693 (M + H) ⁺ .

Example 47

To a suspension of 0.37 g of 3- (£ -aminophenyl) -N- (2-naphthylsulfonyl) -D-alanine (Example 35a) in 20 ml of dioxane, 0.45 ml of an 50% solution of ethyl glyoxylate in toluene. The resulting solution is treated with 0.3 g of 10% palladium on charcoal and hydrogenated for 6 hours at room temperature and under normal pressure. The catalyst is filtered off, the filtrate is evaporated and the residue is reacted in a similar manner to that described in Example 5. Yield: 89 mg of N- [£ - [(R) - ethyl ester hydrochloride) 2 - [[[(RS) -1-amidino-3-piperidinyl] -methyl] -carbamoyl] -2- (2-naphthylsulfonamido) -ethyl] -phenyl] -glycine. EM-FAB: 595 (M + H) ⁺ .

Example 48

In a manner analogous to that described in Example 26, the hydrochloride of (R) -N - [[(RS) -1-amidino-3-piperidinyl] -methyl] -1,2,3,4-tetra- hydro-2- (2-naphthylsulfonyl) -3-isoqu ^ _T 25 the nolinocarboxamide (epimers 1: 1). [06 ^ 539 ~ +76.8 (methanol, c = 0.5%). EM-FAB: 506 (M + H) ⁺ .

Example 49

Analogously to that described in Example 5, the (RS) -N - [[(RS) -1-amidino-3-piperidinyl] - hemisulphite is obtained

-methyl] -3- (o-aminobenzoyl) -2- (2-naphthyl-sulfonamido) -propionamide. EM-FAB: 537 (M + H) ⁺ .

Example 50

The following compounds are prepared in a manner analogous to that described in Example 23:

a) (S) -N - [[(RS) -1-amidino-piperidinyl] -methyl] - -2- (2-naphthyl-sulfonamido - oxo-4-morpholinobutyramide trifluoroacetate. EM-FAB: 531 (M + H) ⁺ ?

b) (R) -N - [[(RS) -1-amidino-3-piperidinyl] -methyl] -hexa-anhydrous-β -2-naphthyl-sulfonamido-Y -oxo-1H-azepine butyramide trifluoroacetate. EM-FAB: 543 (M + H) ⁺ .

c) (S) -N - [[((RS) -l-amidino-3-piperidinyl] -methyl] -hexa-hydro- β -2-naphthyl-sulfonamido-oxo-1- (2H) -azocinobutyramide hydrochloride . EM-FAB: 557 (M + H) ⁺ .

EXAMPLE 51

a) 5 g of potassium diphenylsulfone-3-sulfonate in 50 ml of thionyl chloride are refluxed overnight. The precipitated compound is filtered off and after drying, 3.2 g of diphenylsulfone-3-sulfonyl chloride are obtained.

b) To a solution of 1.52 g of jo-nitro-D-phenylalanine in ml of dioxane are added 6.7 ml of a solution of IN sodium hydroxide and 2.82 g of sodium hydrogen carbonate. Adi.

then a solution of the product prepared in

a) in 119 ml of dioxane and the mixture is stirred overnight at room temperature. Then, the reaction mixture is poured onto ice and extracted with ethyl acetate. Wash the organic phase with water, dry and concentrate. Thus, 1.75 g of 3- (£ -nitrophenyl) -N - [[(m-phenylsulfonyl) -phenyl] -sulfonyl] -D-alanine are obtained.

c) From the acid mentioned before performing techniques si. to those described in Example 6 (e) and g) (R) -N - [[((S) -l-amidino-3-piperidinyl] -methyl] - £ -nitro- - [m - (phenyl-sulfonyl) -benzenesulfonamido] -hydrocinamamide. EM-FAB: 629 (M + H) ⁺ .

Example 52

a) 2.3 g of p> -nitro-D-phenylalanine is suspended in 25 ml of dioxane and treated with 10 ml of a solution of IN sodium hydroxide and 1.7 g of sodium hydrogen carbonate . Dropwise, a solution of 2.6 g of methyl 2-chlorosulfonyl-benzoate in 22 ml of dioxane is added and the mixture is stirred. for 9 hours at room temperature. The reaction mixture is poured into ice-cooled 2N hydrochloric acid and extracted with ethyl acetate. Wash the organic phase with water, dry and evaporate. 3.2 g of N - [[o- (methoxycarbonyl) -phenyl] -sulfonyl] -3- (£ -nitrophenyl) -D-alanine are obtained.

c) The product obtained in paragraph a) is dissolved in 30 ml of tetrahydrofuran, treated with 5.3 ml of hexamethyleneimine and stirred for 5 hours at 80 ° C. Evaporates to

reaction mixture, the residue is taken up in ethyl acetate and stirred again with 2N hydrochloric acid and twice with water. After drying the organic phase, evaporating and chromatography of the residue on silica gel, 0.9 g of N - [[o - [(hexahydro-1H-azepin-l-yl) -carbonyl] -phenyl are obtained ] -sulfonyl] -3- (p-nitrophenyl) -D-alanine.

c) In a manner analogous to that described in Example 5, from the compound prepared in b), (R) -N- [[(RS) -1-amidino-3-piperidinyl] -methyl hydrochloride is obtained ] - - [o- [(hexa-hj.

dro-1H-azepin-1-yl) -carbonyl] -benzenesulfonamido] -p-nitrohydrocinamamide. EM-FAB: 614 (M + H) ⁺ .

Example 53

The following compounds are prepared in a manner analogous to that described in Example 52:

a) (R) -N - [((RS) -1-amidino-3-piperidinyl] -methyl] “θ (“ (£ -t-butyl-benzenesulfonamido) -p-nitrohydrocinamamide. EM-FAB : 545 (M + H) ⁺ .

b) (R) -N - [[((RS) -1-amidino-3-piperidinyl] -methyl] -p-nitro- - (benzo [b] thiophenesulfonamido) -hydrocinamami hydrochloride. IN. FAB: 545 (M + H) ⁺ .

Example 54

Using techniques similar to those described in Examples 90 a) and 23, (βS, 2RS) -N - [[(RS) -1-amidino-3-piperidinyl] -methyl] -2-benzyloxymethyl-- is obtained (R) -N - [(R) -1-amidino-3-piperidinylmethyl] - (£ -iodo-benzenesulfonamido) -indol-3-propionamide 2-naphthyl-sulfone> -42a) 1). EM-FAB: 609 (M + H) ⁺ .

b) (R) -N - [(S) -1-amidino-3-piperidinyl-methyl] - 0 <- <E-iodo-benzenesulfonamido) -indol-3-propionamide £ -toluenesulfonate (1: 1). EM-FAB: 609 (M + H) ⁺ .

c) (R) -l-amidino-3-piperidinylmethyl ester and N- (£ -iodo-phenylsulfonyl) -D-tryptophan (1: 1). EM-FAB: 609 (M + H) ⁺ .

d) N- (£ -iodo-phenylsulfonyl) -D-tryptophan ester (S) -l-amidino-3-piperidinylmethyl (1: 1). EM-FAB: 610 (M + H) ⁺ .

e) (R) -N - [(R) -1-amidino-3-piperidinylmethyl [- - (£ -iodo-benzenesulfonamido) -2-naphthyl-propionamide £ -toluenesulfonate (1: 1). EM-FAB: 620 (M + H) ⁺ .

f) (R) -N - [(S) -1-amidino-3-piperidinyl methyl] - ¢ (- (£ -iodo-benzenesulfonamido) -2-naphthyl-propionamide £ -toluenesulfonate (1: 1). -FAB: 620 (M + H) ⁺ .

g) N- (£ -iodo-phenylsulfonyl) -3- (2-naphthyl) -D-alanine (R) -l-amidino-3-piperidinylmethyl ester (1: 1). EM-FAB: 621 (M + H) ⁺ .

h) N- (£ -iodo-phenylsulfonyl) -3- (2-naphthyl) -D-alanine (S) -l-amidino-3-piperidinylmethyl ester (1: 1). EM-FAB: 621 (M + H) ⁺ .

i) (R) -N - [(R) -1-amidino-3-piperidinylmethyl] -43 ~ (bis ^- iodo-benzenesulfonamido) - £ -nitrohydrocinamamide bisulfite (2: 1). EM-FAB: 615 (Μ + Η) ⁺ .

j) (R) -N - [(S) -1-amidino-3-piperidinylmethyl] -0 ^ - (£ -iodo-benzenesulfonamido) - £ -nitrohydrocinamamide (1: 1) £ -toluenesulfonate. EM-FAB: 615 (M + H) ⁺ .

k) N- (£ -iodo-phenylsulfonyl) -3- (£ -nitrophenyl) D-alani na (1: 1) (R) -l-amidino-3-piperidinylmethyl ester (1: 1). EM-FAB: 616 (M + H) ⁺ ,

l) N- (£ -nodo-phenylsulfonyl) -3- (£ -nitrophenyl) -D-alanine (S) -l-amidino-3-piperidinylmethyl ester (1: 1). EM-FAB: 616 (M + H) ⁺ .

Example 18

The following compounds are prepared using a technique similar to that described in Example 5:

a) (R) -N - [(RS) -1-amidino-3-piperidinylmethyl] -hexa-hydro- θ (-2-naphthyl-sulfonamido-Y-oxo-1H-azepine-l-butyramide bisulfite (epimers) 1: 1) .EM-FAB: 543 (M + H) ⁺ .

b) Methyl ester of 1 - [(R) -23 - [(RS) -1-amidino-3-piperidinylmethylcarbamoyl] -3- (2-naphthyl-sulfonamido) -propyl] -L-proline (epimers 1: 1). EM-FAB: 573 (M + H) ⁺ .

c) 1 - [(R) -3- [RS) -1-amidino-3-piperidinylmethylcarbamoyl] -3- (2-naphthyl-sulfonamido) -propionyl] -L-proline (epimers 1: 1). EMFAB: 559 (M + H) ⁺ .

-67mido-Κ-oxo-4-morpholinabutiramide. EM-FAB: 651 (Μ + Η) ~ * ~. ^z

Example 55

In the presence of 10% palladium on carbon, a solution of the product prepared in Example 54 in a mixture of ethanol / IN hydrochloric acid is hydrogenated for 30 hours under normal conditions. (Β S, 2RS) -N - [[(RS) -1-amidino-3-piperidinyl] -methyl] -2-hydroxymethyl - ^ - 2-naphthyl-sulfonamido- ^ f -oxo- hydrochloride 4-morpholinabutiramide. EM-FAB: 561 (M + H) ⁺ .

Example 56

A) a) Treat a solution of 23.3 g of racemic 2- (aminomethyl) -4-benzyl morpholine in 250 ml of dioxane with 27.1 g of di-t-butyl dicarbonate in 250 ml of dioxane and stir for 17 hours at room temperature. The solvent is then evaporated and the residue is chromatographed on silica gel using methylene chloride / ethyl acetate (3: 1) as eluent. The product is recrystallized from a mixture of methylene chloride / hexane, giving 25.6 g of racemic t-butyl [(4-benzyl-2-morpholinyl) -methyl] -carbamate.

A) b) A solution of the product prepared in (a) is treated in 500 ml of ethyl acetate and 50 ml of acetic acid with 2.6 g of palladium on charcoal and hydrogenated for 5 hours at room temperature. After filtration and evaporation, the residue is dissolved in 230 ml of dimethylformamide, treated with

-6846 ml of triethylamine and 10.8 g of midinosulfonic acid and stir for 20 hours at room temperature. The reaction mixture is then evaporated and the residue is partitioned between ethyl acetate and water. After drying the organic phase and evaporation, the racemic t-butyl [(4-amidino-2-morpholinyl) -methyl] -carbamate hemisulphite is obtained.

A) c) 6.5 g of the compound obtained there is suspended.

nea b) in 50 ml of methylene chloride and treat, at 0 ° C, with 20 ml of trifluoroacetic acid. After 7 hours at 0 ° C, the reaction mixture is evaporated and an azeotropic mixture of the residue is formed with methylene chloride and toluene. Racemic 2- (aminomethyl) -4-morpholinocarboxamidine trifluoroacetate is obtained.

B) A solution of 0.8 g of (S) -β-2-naphthyl-sulfonamido- ^ -oxo-4-morpholinobutyric acid, obtained in a similar manner to that described in Example 23 a) to c), in 16 ml of dimethylformamide, with 0.76 ml of 4-ethylmorpholine, 0.89 g of benzotriazol-1-yloxy-tris (dimethylamino) -phosphonium hexafluoride and 1.16 g of the product obtained in point A) c) and the mixture is stirred for 17 hours at room temperature. The reaction mixture is then treated with 1N hydrochloric acid and evaporated. After chromatography on an RP-18 column using water / acetonitrile as eluent, 0.5 g of (SN - [[((RS) -4-amidino-2-morpholinyl] -methyl] - β -2 hydrochloride is obtained -naftyl-sulfonamido-tf-oxo-morpholinobutyramide EM-FAB: 533 (M + H) ⁺ .

Example 57

In a manner analogous to that described in Example 56, we obtain:

a) (S) -N - [[((RS) -4-amidino-2-morpholinyl] -methyl] -β -2-naphthyl-sulfonamido-hexahydro-oxo-1H-azepine-l-butira hydrochloride mida. MS-FAB: 545 (M + H) ⁺ ;

b) (S) -N-4 - [[((RS) -4-amidino-2-morpholinyl] -methyl] -hexa-hydro-β-2-naphthyl-sulfonamido- ^ -οχο-1- (2H) hydrochloride ) -azocin1-butyramide. EM-FAB: 559 (M + H) ⁺ .

Example 58

In a manner analogous to that described in Example 8, (R) -N - [[(RS) -1-amidino-3-piperidinyl] -methyl] - - (2-naphthyl-sulfonamido) -2 triacetate is obtained -oxo-3-benzoxazolinopropionamide.

EM-FAB: 551 (M + H) ⁺ .

Example 59

The following compounds are prepared using techniques similar to those described in Examples 8 and 56:

a) (R) -N - [[(RS) -4-amidino-2-morpholinyl] -methyl] -2 -2-naphthyl-sulfonamido-2,3-dioxo-1-indolinopropionamide hydrochloride.

EM-FAB: 565 (M + H) ⁺ .

b) (R) -N - [[((RS) -4-amidino-2-morpholinyl] -methyl] -2 -2-naphthyl-sulfonamido-2-oxo-3-benzoxazolinopropionamide hydrochloride.

-70EM.-FAB: 553 (M + H) ⁺

Example 60

A) a) To a solution of 10.0 g of t-butyl (S) -3-aminomethyl-1-piperidinecarboxylate (Example 6 d) in 400 ml of hexane and 100 ml of water is added 3.7 g of tetrabutylammonium hydrogen sulfate and 100 ml of a 1N sodium hydroxide solution. Dropwise, 9.3 ml of benzyl chloroformate are added to this mixture and the resulting mixture is stirred for 3 hours at room temperature. Then separate the organic layer, wash with water, 10% citric acid, water and a saturated solution of sodium hydrogen carbonate, dry and evaporate. T-butyl (S) -3 - [[1- (benzyloxy) -formamide] methyl] -1-piperidinecarboxylate is obtained.

A) b) 11.3 g of the product obtained in paragraph a) are dissolved in 200 ml of ethyl acetate, treated, at a temperature of 4 ° C, with 120 ml of a 4 molar solution of hydrochloric acid in acetate ethyl acetate and stir for 5 hours at room temperature. The reaction solution is then concentrated, the residue is dissolved in 265 ml of dimethylformamide, treated with 18 ml of triethylamine and 4.3 g of formamidinesulfonic acid and stirred for 17 hours at room temperature. Evaporate the solvent, treat the residue with 1N hydrochloric acid, concentrate again and chromatograph on an RP-18 column using water / acetonitrile as eluent. 5.4 g of benzyl [[(S) -1-amidino-piperidinyl] -methyl] -carbamate hydrochloride are obtained.

A) c) In 165 ml of ethanol and 165 ml of IN hydrochloric acid, 6.6 g of the compound obtained in b) are dissolved, treated with 1 g of palladium on charcoal and hydrogenated for 2 hours under normal conditions. After filtration, evaporation and formation of an azeotropic mixture with ethanol, 4.5 g of (S) -1-amidino-3- (aminomethyl) -piperidine dihydrochloride are obtained. MP 252 ° -254 ° C. EM-FAB: 156 (M ⁺ ). [^] D-16.9 ° (c = 1.0, water).

B) Treat a solution of 1.9 g of N- (2-naphthylsulfonyl) -3- (2,3-dioxo-1-indolinyl) -D-alanine in 30 ml of dimethylformamide with 2.3 ml of 4-ethyl-morpholine, 2.0 g of benzotriazol-1-yloxy-tris (dimethylamino) -phosphonium hexafluorophosphate and 1.0 g of the product obtained in point (a) (c) and stir for 20 hours at room temperature . The reaction mixture is concentrated, treated with 1N hydrochloric acid, evaporated again and the residue is chromatographed on silica gel using ethyl acetate / acetone / acetic acid / water (16: 2: 1 as eluent): 1). 0.8 g of (R) -N - [(S) -1-amidino-3-piperidinylmethyl] - - (2-naphthyl-sulfonamido) -2,3-dioxo-1-indolinopropionamide acetate are separated. EM-FAB: 563 (M + H) ⁺ .

Example 61

The following compounds are obtained using techniques similar to those described in Examples 8 and 60:

a) (R) -N - [[((S) -1-amidino-3-piperidinyl] -methyl] -2 -2-naphthyl-sulfonamido-2-oxo-3-benzoxazolidinopropionamide hydrochloride. EM-FAB. 551 (M + H) ⁺ .

b) (R) -N - [[(S) -1-amidino-3-piperidinyl] -methyl] -5-bromo- (/ -2-naphthyl-sulfonamido-2,3-dioxo-l tetraacetate -indolinopropionamide EM-FAB: 643 (M + H) ⁺ ;

c) (R) -N - [[((S) -1-amidino-3-piperidinyl] -methyl] -5-methyl--2-naphthyl-sulfonamido-2,3-dioxo-1-indolinopropio acetate namide. EM-FAB. 577 (M + H) ⁺ ;

d) (R) -N - [[((S) -l-amidino-3-piperidinyl] -methyl] - - [(£ -iodophenyl) -sulfonyl] -2,3-dioxo-1-indolinopropionamide hydrochloride.

MS-FAB: 639 (M + H) ⁺ ;

e) (R) -N - [[((S) -1-amidino-3-piperidinyl] -methyl] - - (o-nitrobenzenesulfonamido) -2,3-dioxo-1-indolinopropionamide hydrochloride. EM-FAB: 558 (M + H) ⁺ .

Example 62

a) With stirring, a solution of 21.4 g of 2-naphthylsulfonyl chloride in 200 ml of ether is added dropwise to a solution of 15 g of N-ZL-2,3- acid diaminopropionic in 189 ml of IN sodium hydroxide solution. The mixture is stirred for an additional 6 hours. - The reaction mixture is then poured into ice-cooled 2N hydrochloric acid and extracted with ethyl acetate. Wash the organic phase with water, dry and evaporate. After chromatography of the residue on silica gel using methylene chloride / / methanol / acetic acid (94: 5: 1) as a result, 17.9 g of N - [(benzyloxy) -carbonyl] -3- (2 are obtained) -naphthyl-sulfonamido) -L-alanine.

b) From the compound obtained in point a), in a dwarf-73-

as described in Example 5, the [(S) —1 - [[[(RS) —1— -amidino-3-piperidinyl] -methyl] -carbamoyl-2- (2-naphthyl-sulfonamido) - benzyl ethyl carbamate. EM-FAB: 567 (M + H) ⁺ .

Example 63

a) A solution of 1.1 g of the product prepared in Example 62 (b) in 22 ml of IN hydrochloric acid and 11 ml of ethanol is treated with 0.2 g of palladium on carbon and hydrogenated for 5 hours under normal conditions. After filtration and evaporation, 0.96 g of (S) - [[(RS) -1-amidino-3-piperidinyl] -methyl] -2-amino-3- (2-naphthyl-sulfonamido) dihydrochloride are obtained -propionamide. EM-FAB: 433 (M + H) ⁺ .

b) This is a 0.95 g solution of the product obtained there. nea a) in 20 ml of dimethylformamide with 0.24 ml of 4-ethylmorphine and 0.3 g of phthalic anhydride and stir for 6 hours at 0 ° C. The reaction mixture is evaporated and the residue is chromatographed on an RP-18 column using water / acetonitrile as eluent. 0.3 g of o - [[(S) -l-- [[[(RS) -l-amidino-3-piperidinyl] -methyl] -carbamoyl] -2- (2-naphthyl-sulfonamido) are obtained ) -ethyl] -carbamoyl] -benzoic, EM-FAB: 581 (M + H) ⁺ .

Example 64

A solution of 1.4 g of the product prepared in Example 63 (a) in 28 ml of dimethylformamide is treated with 1.05 ml of 4-ethylmorpholine, 1.23 g of benzotriazole-1-yloxy-tris hexafluorophosphate (dimethylamino ) -phosphonium and 0.95 g of o- (benzyloxy) -benzoic acid and stir all night at

-74 pounds environment. Evaporate the reaction mixture and share *

The residue is partitioned between ethyl acetate and water. The organic phases are dried and evaporated and the residue is chromatographed on silica gel using ethyl acetate / acetone / acetic acid / water (16: 2: 1: 1) as eluent. 0.2 g of (S) -2-N- [o- (benzyloxy) -benzamido] -3- (2-naphthylsulfonamido) -N - [[(RS) -l-amidino- 3-piperidinyl] -methyl] -propionamide. EM-FAB:

643 (M + H) ⁺ .

Example 65

a) Using a technique similar to that described in Example 64 but using t-butyl- (R) -2-piperidinecarboxylic acid instead of o- (benzyloxy) -benzoic acid, (R) -2- trifluoroacetate is obtained [[(S) -1 - [[[(RS) -l-amidino-3-piperidinyl] -methyl] -carbamoyl] -2- (2-naphthyl-sulfonamido) -ethyl] -carbamoyl] -1-piperi dinocarboxylate of t-butyl. MS-FAB: 644 (M + H) ⁺ .

b) A solution of 300 mg of the product prepared in (a) in 5 ml of ethyl acetate is treated with 5 ml of a 4 molar solution of hydrochloric acid in ethyl acetate. After stirring for 3 hours at room temperature, the suspension is evaporated and (R) -N- (S) -1 - [[[((RS) -1-amino dino-3-piperidinyl] - dihydrochloride is obtained methyl] -carbamoyl] -2- (2-naphthylsulfonamido) -2-piperidinecarboxamide. EM-FAB: 544 (M + H) ⁺ .

Example 66

A solution of 120 mg of the product prepared in Example 64 in 12 ml of acetic acid is treated with 50 mg of palladium

on coal and hydrogen for 6 hours under normal conditions. After filtration and evaporation, 80 mg of (S) -N - [[((RS) -1-amidino-3-piperidinyl] -methyl] -2- (2-hydroxybenzamido) -3- (2- naphthyl-sulfonamido) -propionamide. EM-FAB: 553 (M + H) ⁺ .

Example 67

a) In a manner analogous to that described in Example 6a) to e) the product obtained in Example 62a) is reacted. (S) -3 - [[[N - [(benzyloxy) -carbonyl] -3- (2-naphthylsulfonamido) -L-alanyl] -amino] -methyl] -1-piperidinecarboxylate is obtained butyl. EM-FAB: 525 (M + H) ⁺ .

b) A solution of 3.0 g of the product obtained in (a) in 80 ml of ethyl acetate / acetic acid (1: 1) is treated with 0.8 g of palladium on carbon and hydrogenated under normal conditions for 48 hours. After filtration and evaporation of this], the residue is seen in 25 ml of dimethylformamide, 1.6 ml of 4-ethylmorpholine and 0.81 g of isatonic anhydride and agi are added. the mixture was made for 16 hours at 80 ° C. Evaporate the solvent and partition the residue between ethyl acetate and water. The organic phase is washed with water, dried and the residue is chromatographed on silica gel using an eluent methylene chloride / ethyl acetate (3: 1). 1.3 g of t-butyl (S) -3 - [[[N-anthranylyl-3- (2-naphthylsulfonyl) -L-alanyl] -amino] -methyl] -1-piperidinecarboxylate are separated. EM-FAB: 610 (M + H) ⁺ .

*

c) From the product isolated according to point b), using a technique similar to that described in Example 6, point f) and g), the hemisulfite of N - [(Sl - [[[(S) -1 -ami dino-3-piperidinyl] -methyl] -carbamoyl] -2- (2-naphthyl-sulfonamido) -ethyl] -o-aminobenzamide EM-FAB: 552 (M + H) ⁺ .

Example 68

Using techniques similar to those described in Example 23 a) to c) and Example 60 b) and using ethyl trans-4-methyl-2-piperidinecarboxylate instead of benzylamide, (2RS, 4R) -1 acetate is obtained - [(S) -3 - [[[(S) -1-amidino-3-piperidinyl] -methyl] -carbamoyl] -2- (2-naphthyl-sulfonamido) -propyl nil] -4-methyl-2- ethyl piperidinecarboxylate (epimers 1: 1). EM-FAB: 615 (M + H) ⁺ .

Example 69

By treating the product prepared in the Example with a methanolic solution of sodium hydroxide, the (2RS, 4R) -1- [N ^ - [[(S) -l-amidino-3-piperidinyl] 2 acid is obtained

-methyl] -N - (2-naphthylsulfonyl) -L-asparaginyl] -4-methyl-2-pyridinecarboxylate (epimers 1: 1). EM-FAB: 587 (M + H) ⁺ .

Example 70

a) Dropwise, add 22.4 ml of 2N sodium hydroxide, at 10 ° C, to a solution of 5 g of ester

D-aspartic acid β-benzyl and 5.07 g of 2-naphthylsulfonyl chloride in 80 ml of dioxane cooled to 10 ° C. The reaction mixture is then stirred for 2 hours at room temperature and then treated with 25 ml 1N hydrochloric acid. After evaporation of dioxane, the residue is taken up in ethyl acetate and washed with water. After drying and evaporating the ethyl acetate phase, 9.1 g of 4-benzyl-N- (2-naphthylsulfonyl) -D-aspartate are obtained. Rf = 0.53 using ethyl acetate / glacial acetic acid as eluent (0.97: 0.03).

b) With stirring, add to the product prepared in point a) in 100 ml of dimethylformamide 3.72 ml of Hunig's base 9.67 g of benzotriazol-l-yl-oxy-tris (dimethylamino) -phosphonium hexafluorophosphate and 4.68 g of t-butyl (S) -3-aminomethyl-1-piperidinecarboxylate. The reaction mixture is stirred for 4 hours, then taken up with ether and the ethereal phase is washed with water. After drying and evaporating the ether phase, the residue is chromatographed on silica gel using ether / hexane (9: 1) as eluent. 9.1 g of (R) -3 - [[[((S) -1- (t-butyloxycarbonyl) -3-piperidinyl] -methyl] -carbamoyl] -3- (2-naphthyl-sulfonamido) - are obtained benzyl propionate. Rf = 0.35 using ether / hexane (9: 1) as eluent.

c) Dissolve in 60 ml of methanol 3.0 g of the product prepared in b) and after the addition of 10% palladium on charcoal, hydrogenate at room temperature under normal pressure. After 8 hours, the catalyst is filtered off and the methanolic solution is concentrated. 2.38 g of (R) -3 - [[[(S) -1- (t-butoxycarbonyl) -3-piperidinyl] -methyl] -carb are obtained

-/s-

moil] -3- (2-naphthyl-sulfonamido) -propionic. Rf = 0.08 using ethyl acetate as eluent.

d) Cool to a temperature of -23 ° C, 1 g of the carboxylic acid prepared in line c) in 18 ml of methylene chloride and successively add 0.25 ml of N-methylmorpholine and 0 , 3 ml of isobutyl chloroformate. The reaction mixture is then stirred at -23 ° C and treated with 0.36 ml of ethyl piperidine-3-carboxylate. The reaction mixture is then taken up in 100 ml of ether. The ethereal solution is washed with 1N hydrochloric acid and water. After drying and evaporating the ether phase, the residue is chromatographed on silica gel using ethyl acetate / hexane (4: 1) as eluent. 917 mg of (R, S) -1 - [(R) -3 - [[[((S) -1- (t-butoxycarbonyl) -3-piperidinyl] -methyl] -carbamoyl-3- (2 -naphthyl-sulfonamido) -pro pioneyl] -3-piperidinecarboxylate ethyl. Rf = 0.4 using ethyl acetate / hexane (4: 1) as eluent.

c) With stirring, 1.2 ml of trifluoroacetic acid are added to a 400 mg solution of the product prepared in

d) in 9.5 ml of methylene chloride. The methylene chloride and trifluoroacetic acid are then evaporated at 50 ° C. The residue is dissolved in methanol and the methanolic solution is treated with 0.42 ml of triethylamine and 150 mg of formamidinesulfonic acid. The reaction mixture is then stirred for 8 hours at room temperature. More, three times, at two hour intervals, 0.09 ml of triethylamine and 75 mg of formamidinesulfonic acid are added. The reaction mixture is concentrated, the residue is suspended in 20 ml of Takeda / ethyl acetate solution (1: 1) [Takeda solution = ethyl acetate / acetone / water / glacial acetic acid (6: 2 : 1: 1)] and filter. The filtrate is concentrated and the residue is chromatographed on silica gel using Takeda / ethyl acetate (1: 1) as eluent. From this chromatography 114 mg of (RS) -1 - [(R) - [[(S) -l-amidino-3-piperidinyl] -methyl] -carbamoyl] -3- (2-naphthyl) acetate -sulfonamido) -propionyl] -3-piperidinecarboxylate.

Rf = 0.34, MS (EI): 601 (M + H) ⁺ .

Example 71

The following compounds are obtained in a manner analogous to that described in Example 70:

a) [(R) -1 - [(S) -3 - [[(S) -1-amidino-3-piperidinyl] -methyl] -carbamoyl] -3- (2-naphthyl-sulfonamido) -propionyl acetate ] -3-piperidinyl] -methyl. Rf = 0.61 using a Takeda solution as eluent. EM-FAB: 601 (M + 1);

b) [(S) -1 - [(S) -3 - [[(S) -1-amino-3-piperidinyl] -methyl] -carbamoyl] -3- (2-naphthyl-sulfonamido) β-tosylate -propionyl] -3-pipe ridinil] -methyl (1: 1). Rf = 0.29 using a Takeda solution as eluent. EM-FAB: 601 (M + 1);

c) (RS) -1 - [(R) -3 - [[((S) -1-amidino-3-piperidinyl] -methyl] -carbamoyl] -3- (2-naphthyl-sulfonamido) -propionyl acetate] Methyl-4-oxo3-piperidinecarboxylate (1: 1). Rf = 0.27 using a Takeda solution as eluent. EM-FAB: 601 (M + 1);

d) [(S) -1- [(R) -3- [[(S) -l-amidino-3-pi-peridinyl] -methyl] -carbamoyl] -3- (2-naphthyl- acetate) sulfonamido) -acetyl] -80-3-piperidinyl] -methyl. Rf = 0.29 using a Takeda solution as eluent. EM-FAB: 601 (M + 1);

e) [(R) -1 - [(R) -3 - [[(S) -1-amidino-3-piperidinyl] -methyl] -carbamoyl] -3- (2-naphthyl-sulfonamido) acetate -aceyl] -3-piperidinyl] -methyl. Rf = 0.35 using a Takeda solution as eluant. EM-FAB: 601 (M + 1);

f) (RS) -1- [(R) - [[(S) -1-amidino-3-piperidi diethylacetate. nil] -methyl] -carbamoyl] -3- (2-naphthylsulfonamido) -propionyl] -3-piperidinecarboxamide. Rf = 0.3 using a Takeda solution as eluent. MS-FAB: 628 (M + 1);

g) [(S) -1 - [(S) -3 - [[[((S) -1-amidino-3-piperidinyl] -methyl] -carbamoyl] -3- (2-naphthyl-sulfonamido) isobutyrate acetate ) -propionyl] -3-piperidinyl] methyl. Rf = 0.43 using a Takeda solution as eluent. MS (EI): 629 (M + 1);

h) [(S) -1 - [(S) -3 - [[[((S) -1-amidino-3-piperidinyl] -methyl] -carbamoyl] -3- (2-naphthyl-sulfonamido) butyrate acetate ) -propionyl] -3-piperidinyl] -methyl. Rf = 0.47 using a Takeda solution as eluent. EM-FAB: 629 (M + 1);

i) (3R, 4R) -4-acetoxy-l - ((R) -3 - [[[(S) -1-amidino-3-piperidinyl] -methyl] -carbamoyl] -3- (2- naphthylsulfonamido) -propionyl] -3-piperidinecarboxylate (1: 1) Rf = 0.21 using a Takeda solution as an eluent EM-FAB: 659 (M + 1);

j) (3S, 4S) -4-acetoxy-1 - [(R) -3 - [[[(S) -1-amidino-3-piperidinyl] -methyl] -carbamoyl] -3- (2- naphthylsulfonamido) -propionyl] -3-piperidinecarboxylate (1: 1). Rf = 0.24

81 using a Takeda solution as eluent. EM-FAB: 659 (M + 1);

For the preparation of the products of subparagraphs a), b), g) and h), S-aspartic acid benzyl ester is used instead of D-aspartic acid β-benzyl ester (Example 70 a)).

The intermediate compounds used in the preparation of the products in points a), b), d) e), i) and j) are synthesized according to the following method:

For 30 minutes, 2.0 g of t-butyl (S) -3-hydroxymethyl-1-piperidinecarboxylate or t-butyl (R) -3-hydroxymethyl-piperidinecarboxylate are stirred together with 0.88 ml of acetic anhydride , 26.3 mg of dimethylaminopyridine and 3.0 ml of pyridine. The reaction mixture is then taken up with ether and the ether is washed with 20% citric acid, a saturated solution of sodium hydrogen carbonate and with water. After drying and evaporating the ether phase, 2.44 g of the product (Rf = 0.85 using ether) is dissolved in 50 ml of methylene heat and treated with 12 ml of trifluoroacetic acid. co. The reaction solution is stirred for 30 minutes and then concentrated to dryness. In point (d) the trifluoroacetic acid salt of (S) - or (R) -3-acetoxymethyl-1-piperidinecarboxylic acid is used (Rf = 0.14 using a Takeda solution as eluent) with an equivalent amount triethylamine.

The intermediate compounds used in the synthesis of the products of points g) and h) are prepared as follows:

To 3.0 g of t-butyl (S) -3-hydroxymethyl-1-piperidinecarboxylate are added 170 mg of dimethylaminopyridine and 3.4

mg of pyridine. Dropwise, 1.66 ml of isobutyryl chloride are added. The reaction mixture is then concentrated. The residue is taken up in ether and the ether phase is washed successively with 20 ml of citric acid, water, a solution of sodium hydrogen carbonate and with water. After drying and evaporating the ether phase, 3.9 g of t-butyl (S) -3-isobutyroxymethyl-1-piperidinecarboxylate (Rf = 0.87 using ether) are obtained. 3.09 g of this ester are dissolved in 80 ml of methylene chloride and treated with 20 ml of trifluoro acetic acid. After stirring for 30 minutes, the solution is concentrated. 30 ml of methanol are added to the residue and then a saturated sodium hydrogen carbonate solution is added dropwise. The aqueous phase is extracted with methylene chloride and the methylene chloride extracts are dried and concentrated. 2.82 g of (S) -3-isobutyroxymethyl-1-piperidinecarboxylic acid trifluoroacetic acid salt are obtained. Rf = 0.4 used as a Takeda solution as eluant.

Using a similar method, the trifluoroacetic acid salt of (S) -3-butyroxymethyl-1-piperidinocarboxylic acid is obtained. Rf = 0.4 using a Ta keda solution as eluent.

Example 72 ^a ) Dropwise, 14.4 ml of triethylamine are added to 6.91 g of glycine t-butyl ester hydrochloride and 12.1 g of 2-naphthylsulfonyl chloride in 70 ml of chloride methylene.

The reaction mixture was then diluted with 200 ml of ether. The organic phase is washed with 1N hydrochloric acid and water. After drying and evaporation, the residue is suspended in ether and filtered with suction. After drying the crystals, 11.57 g of N- (2-naphthylsulfonyl) glycine t-butyl ester are obtained. Rf = 0.49 using ether / hexane (2: 1) as eluent.

(b) In 10 ml of methylene chloride, 1 g of the product prepared in (a), 923 mg of dansyl chloride, 0.48 mg of triethylamine and 418 mg of dimethylformamide are mixed simultaneously. Treat the reaction mixture with 100 ml of ether and wash with 1N hydrochloric acid and water. After drying and evaporation, 1.67 g of N - [[5- (dimethylamino) -1-naphthyl] -sulfonyl] -N- (2-naphthyl-sulfonyl) -glycine are obtained. Rf = 0.33 using methylene chloride / n-hexane (9: 1) as eluent.

c) At a temperature between 0 ° and 5θΟ, gaseous hydrochloric acid is made using a solution of the product prepared in (b) in 17 ml of methylene chloride. After concentrating the reaction solution, 1.7 g of carboxylic acid are obtained [Rf = 0.72 using ethyl acetate / glacial acetic acid (97; 3)] as eluent. To a solution of this product in 17 ml of methylene chloride, at room temperature, 844 mg of dicylhexylcarbodiimide (DCC) are added. Then 877 mg of t-butyl (S) -3-aminomethyl-1-pyridinecarboxylate dissolved in 3 ml of methylene chloride are added. The reaction mixture is filtered, the filtrate is evaporated and the residue is chromatographed on silica gel using methylene chloride / ether (9: 1) as eluent. 0.82 g of (S) —3— are obtained

- [[N - [[5- (dimethylamino) -1-naphthyl] -sulfonyl] -N- (2-naphthyl-sulfonyl) -glycyl-amino] -methyl] -1-piperidinecarboxylate.

-84f * [Rf = 0.2 using methylene chloride / ether (9: 1) as eluent]. The resulting product (0.82 g) is converted using a technique similar to that described in Example 70 (e), into 316 mg of N - [[((S) -l-amidino-3-piperidinyl] -methyl acetate ] -2 - [[[5-dimethylamino) -1- (2-naphthylsulfonyl) -amino] -acetamide.

Rf = 0.46 using a Takeda solution as eluent. EMFAB: 637 (M + 1).

Example 73

In a similar way to that described in Example 30, but used. using 2-thienylglyoxalic acid, benzoic acid and benzyl chloroform, respectively, instead of phenylglyoxalan acid. (Example 30 g), we obtain:

a) (R) -N - [[((S) -1-amidino-3-piperidinyl] -methyl] -2- (2-naphthyl-sulfonamido) -3- (-oxo-2-thiophenoacetamido) £ -toluenesulfonate -propionamide (1: 1). MS-FAB: 571 (M + H) ⁺ ;

b) N - [(R) -2 - [[[((S) -l-amidino-3-piperidinyl] -methyl] -carbamoyl-2- (2-naphthyl-sulfonamido) -ethyl] -benzamide £ -toluenesulfonate (1: 1). MS-FAB: 537 (M + H) ⁺ , bzw;

a) Benzyl [(R) -2 - [[[((S) -1-amidino-3-piperidinyl] -methyl] -carbamoyl] -2- (2-naphthyl-sulfonamido) -ethyl] -carbamate ( 1: 1). EM-FAB: 567 (M + H) ⁺ .

EXAMPLE 74

From the product prepared in Example 27 by treatment with an aqueous solution of sodium hydroxide, ο - [[(R) - - [[[((RS) -l-amidino-3-piperidinyl] - me- * tyl] -carbamoyl] - £ -nitrophenyl] -sulfamoyl] -benzoic. EM-FAB: 533 (M + H) ⁺ .

Example 75

Using techniques similar to those described in Examples 68 and 69, (R) -4 - [(S) -3 - [[[((S) -amidino-3-piperidinyl] -methyl] -carbamoyl-2- (2-naphthyl-sulfonamido) -propionyl] hexahydro-1,4-oxazepine-3-carboxylic. EM-FAB: 589 (M + H) ⁺ .

Example 76

By techniques similar to those described in example 52 (but using 2-naphthylsulfonyl chloride) and in Example 60, the acid £ - [(RS) -2 - [[[(S) -l-amidino-3 -piperi dinyl] -methyl] -carbamoyl] -2- (2-naphthyl-sulfonamido) -ethyl] -benzoic. EM-FAB: 538 (M + H) ⁺ .

Example 77

Using a technique similar to that described in Example 43, 4 '- [(R) -2 - [[[(S) -1-amidino-piperidinyl] -methyl] -carbamoyl] -2- (2- naphthylsulfonamido) -ethyl] -succinalid. EM-FAB: 609 (M + H) ⁺ .

For the preparation of pharmaceutical compositions such as tablets or capsules, compounds of general formula I or their salts or solvation products can be used. These compositions are prepared using conventional techniques and have the following composition

EXAMPLE A Per pill Active substance 200 mg Microcrystalline cellulose 155 mg Cornflour 25 mg Baby powder 20 mg Hydroxypropylmethylcellulose 20 mg 420 mg

EXAMPLE B Per capsule Active substance 100.0 mg Cornflour 20.0 mg Lactose 95.0 mg Baby powder 4.5 mg Magnesium stearate 0.5 mg 220.0 mg

Claims (19)

1.- Process for the preparation of compounds of general formula in which R represents an aryl, heteroaryl or heterocycle group; T represents an oxygen atom or a CH ₂ group; L represents an oxygen atom or an NH group; X represents a hydrogen atom or a group -CH ₂ COOH, -CH ₂ COO-alkyl, -CH ₂ CO- (tetra to heptamethyleneimino) or -CH ₂ CONH ₂ eventually N-mono- or N-di-alkylated alkyl radical comprising as an alkyl group C ^ _ _4; and M represents a benzyl-OCONHCH ₂ CH = or -CH ₂ (benzyl-OCONH) CH- group or a group of the general formula r · - (ch ₂ ) ^ _ ₂ ch =, R'-COCH ₂ CH =, R -COCH ₂ CH =, R '(CO) _1-2 NHCH ₂ CH =, -CH ₂ [R' - (CO) _1-2 NH] CH- or -CH (CO-Q) CH ₂ ~ where R 'represents an aryl group, heteroaryl, cycloalkyl or heterocycle, R represents a tetra- heptamethyleneimino group possibly containing up to 2 substituents chosen from oxo, -COO- ^C 6 alkyl groups - (CH ₂ Q ₄ OH, - (CH ₂ ) Q 4 OCO-C ₄ _ ₄ alkyl or carbamoyl possibly having one or two alkyl groups and Q represents a benzyl mino or tetra-heptamethyleneimino group which may be interrupted by an oxygen or sulfur atom and possibly also including up to two substituents chosen from alkyl groups, COOH, -COO-C _1-4 alkyl, -CH ₂ OH or -CH ₂ 0-benzyl; or -N (X) -M- represents an isoquinolylene group optionally substituted in the phenyl nucleus or a group of general formula -N (SO ₂ ~ Rq) -CH ₂ - in which R has the meanings defined above for the symbol R, and of the their hydrates or solvation products and their salts acceptable under the physiological point of view, characterized by the fact (a) that a compound of the general formula R-SO ₂ N (X) -M-COOH (is reacted) ( II) in which R, X and M have the meanings defined before, comprising a protected carboxyl group present in any of the groups represented by the symbols X, R or M, with a com- L and T have the meanings defined before, or a salt thereof, or (b) to react a compound of the general formula in which R, X, M, L and T have the meanings defined before, with an amidination reagent, or (c) of reacting a mine of general formula ο in which R, X, L and Τ’. Have the meanings defined before, with an acid of general formula R'— COOH in which R 'has the meanings defined above, or a functional derivative thereof, and (d) to eventually modify, from a functional point of view, the reactive group present in the radical represented by the symbol M of a compound of general formula I, and ( e) eventually converting a compound of formula I into a physiologically acceptable salt thereof or eventually converting a salt of a compound of formula I into a free acid or base. 2. A process according to the preparation of compounds of the formula of general claim 1 for NH in which R, L and T have the meanings defined in claim 1; X * represents a hydrogen atom or a -CE ^ COOH, -CH ₂ COO-C ₄ _ alkyl, -C 6 ^ CO- (tetra- heptamethyleneimino) or -CH ₂ CONH ₂ optionally N-mono or N- dialkylated having an alkyl group as an alkyl radical and M 'represents a group of general formula R' - (CH ₂ ) _1-2 CH =, R'-COCH ₂ CH = or -CH (CO-Q ') CH ₂ - where R' has the meanings defined above in claim 1 and Q * represents a benzylmino, morpholino or tetra-aetapethyleneimino group, or -N (X ') - M' represents an isoquinolylene group possibly substituted in the phenyl core, or its hydrates or solvation products and its physiologically acceptable salts, characterized by the fact that correspondingly substituted starting compounds are used. Process according to claim 2 for the preparation of compounds of general formula IA in which X 'represents a hydrogen atom and R, M', L and T have the meanings defined in claim 2, characterized in that if correspondingly substituted starting compounds are used. 4.- Process according to claim 1, for the preparation of compounds of general formula in which R, L and T have the meanings defined in claim 1; and · M represents a benzyl group -OCONHCH ₂ CH = or -CH ₂ (benzyl-OCONH) CH- or a group of the general formula r-coch ₂ ch =, r ¹ - (co) _1-2 nhch ₂ ch =, -CH ₂ [R '- (CO) _1-2 NH1CH- or -CH (COQ) CH ₂ - where R * and R ”have the meanings defined in claim 1 and Q represents a tetra- to heptamethyleneimino group which may be interrupted by an oxygen or sulfur atom and also optionally containing up to two substituents, chosen from groups C1-4 alkyl, COOH, -COO-C4 alkyl, -CH ₂ OH or -CH ₂ O-benzyl, characterized because correspondingly substituted starting compounds are used. 5. A process according to claim 1 for the preparation of compounds of general formula I in which R, L, T, M, or -N (X) -M- and X have the meanings defined in claim 1 except that X does not represent a hydrogen atom, characterized in that correspondingly substituted starting compounds are used. 6. The process of claim 1 for the preparation of compounds of formula I in which R represents an aryl group, especially a naphthyl, hydroxynaphthyl, 4-biphenyl, 2-anthryl, iodophenyl, nitrophenyl, benzyloxyphenyl group, dimethoxyphenyl, 4-methoxy-2,3,6-trimethylphenyl, 2,4,6-triisopropylphenyl, carboxyphenyl, methoxycarbonylphenyl, benzyloxynaphthyl, phenylsulfonylphenyl, hexahydroazepinoylphenyl or t-butylphenyl, characterized by the fact that they use correspondingly substituted initial compounds. 7. A process according to claim 1 for the preparation of compounds of the general formula I in which R represents a heteroaryl group, especially a 3-methyl-8-quinoline group, 5- (1-methyl-5- trifluoromethylpyrazol-3-yl) -2-thienyl or benzothienyl, characterized in that correspondingly substituted starting compounds are used. 8. Process according to claim 1 or 2, for the preparation of compounds of general formulas I or IA in which R represents a heterocyclic group, especially a group 38 -methyl-1,2,3,5-tetrahydro-8-quinolyl, characterized in that correspondingly substituted starting compounds are used. 9. A process according to claim 1 for the preparation of compounds of formula I in which —N (X) -M represents an isoquinol-ylene or N-dimethylaminonaphylsulfonylaminomethylene group, characterized in that correspondingly substituted starting compounds are used . 10. A process according to claim 1 or 2 for the preparation of compounds of the general formula I or IA in which X represents a hydrogen atom or a CI COCOOH group, characterized in that corresponding starting compounds are used. replaced. 11. A process according to claim 1 for the preparation of compounds of general formula I in which M represents a group of general formula R '- (CH ₂ ) ^ _ ₂ CH =, especially a group 3-indolylethylidene, 2.3-dioxo-1-indolinylethylidene; phenethylidene; 1.4- dioxo-5H-2,5-benzo-diazepin-5-ylethylidene, (fluoro, chloro, iodo, cyano, nitro, amino, carboxy, alkoxy (C ^ _ ^) - carbonyl or hydroxy) -phenethylidene; hexilpropilideno cyclohexane, decaliletilideno, imidazoliletilideno, tieniletilideno, (methyl, bromo, fluoro or carboxymethyl) -3-indoliletilideno, naftiletilideno (etoxicarbonilcarbonilamino, metoxicarboniletilcarbonilamino, benziloxicarboniletilcarbonilamino, ethoxycarbonylamino, benzoilcarbonilamino, carboxibenzoilamino, metoxietoxiacetamido, acetamido, carboxicarbonilamino car boxipropionilamino, tolyl sulfonamido, iodophenyl-sulfonamido, carboxyphenyl-sulfonamido or ethoxycarbonylmethylamino) phenethylidene, oxobenzoxazolinetylidene or 5-bromo- or 5-methyl-2,3-dioxo1-indolinylethylidene, characterized in that correspondingly substituted starting compounds are used. 12. A process according to claim 1 for the preparation of compounds of general formula I in which M represents a group of general formula (R * or RJCOC ^ CHs, especially a hexahydroazepinoethylidene group, (methoxycarbonyl or carboxy) - pyrrolidinoethylidene, 3,4-dihydro-2 (1H) -isoquinolinoethylidene, (nitro, amino, iodine or formamide) -benzylethylidene, morpholinoethylidene, heptahydroxycinoethylidene, (ethoxycarbonyl, acetoxymethyl, dimethylcarbamoyl, isobutyryloxymethyl or butyryloxyethyl) 3-methoxycarbonyl-4-oxopiperidinoethylidene or 4-acetoxy-3-ethoxycarbonylpiperidinoethylidene, characterized by the fact that correspondingly substituted initial compounds are used. 13. A process according to claim 1 for the preparation of compounds of general formula I in which M represents a group of general formula R '- (CO) ₁ _ ₂ NHCH ₂ CH =, especially a benzoylcarboxamidoethylidene, thienoylcarboxamidoethylidene group, benzoylamidoethylidene or benzyloxycarboxamidoethylidene, characterized in that correspondingly substituted starting compounds are used. 14. A process according to claim 1 for the preparation of compounds of general formula I in which M represents a group of general formula -CH ₂ [R '- (CO) ^ _ ₂ NH] CH-, especially a group 2- (carboxybenzoylamido) ethylene; 2- (benzyloxybenzylaryl acid) ethylene; 2- (2-piperidinecarboxamido) -ethylene; 2- (hydroxybenzoylamido) ethylene; or 2- (aminobenzoyl starch) ethylene, characterized by the fact that correspondingly substituted starting compounds are used. 15. A process according to claim 1 for the preparation of compounds of general formula I in which M represents a group of general formula -CH (CO-Q) CH ₂ -, especially a group 1- (benzylaminocarbonyl) ethylene; 1- (hexahydroazepinoyl) ethylene; 1- (morpholinoyl) ethylene; 1- (heptahydroazocinoyl) ethylene; 1- [2- (benzyloxymethylmorpholinyl)] ethylene; 1- [2- (hydroxymethylmorpholine) ethylene; 1- (2-ethoxycarbonyl-4-methylpiperidinoyl) ethylene; 1- (2-carboxy-4-methylpiperidinoyl) ethylene; or 1- (3-carboxy-hexahydro-1,4-oxazepinoyl) ethylene, characterized in that correspondingly substituted starting compounds are used. 16. A process according to claim 1, 2 or 6 for the preparation of compounds of general formulas I or IA in which R represents an aryl group, especially a naphthyl or nitro- or iodophenyl group, h represents an NH group and the asymmetric carbon atom in the piperidine or morpholine nucleus has the (S) configuration, characterized by the fact that they are used with correspondingly substituted starting positions. 17. Process according to claim 1 for the preparation of compounds of the general formula IC in which A represents an aryl, aryl or heterocycle group, especially a phenyl, nitrophenyl, indolyl, 2,3-dioxo-1-indolinyl or aminobenzoyl group, characterized in that correspondingly substituted starting compounds are used. 18.- Process according to claim 1 or 2, for the preparation of (R) -N- [(RS) -1-amidino-3-piperidinylmethyl] -a- (2-naphthyl-sulfonamido) -2,3 -dioxo-1-indolinopropionamide, · (R) -N- [(RS) -1-amidino-3-piperidinylmethyl] -a- (2-naphthylsulfonamido) -o-nitrohydrocinamamide? (R) -N- [(RS) -l-amidino-3-piperidinylmethyl] -a- (o-nitrobenzene-sulfonamido) indole-3-propionamide7 (R) -N- [(S) -l-amidino-3 -piperidinylmethyl] -a- (p-iodo-benzene-sulfonamido) indole-3-propionamide7 (R) -N- [(S) -1-amidino-3-piperidinylmethyl] -a- (p-iodobenzene-sulfonamido) -p-nitrohydrocinamamide 7 (R) -N- [(RS) -1-amidino-3-piperidinylmethyl] -3- (o-aminobenzoyl) - (2-naphthylsulfonamido) propionamide7 N- [(R) -a- [[(S) -l-amidino-3-piperidinyl] methylcarbamoyl] -phenethyl] -N- (2-naphthylsulfonyl) glycine7 (R) —n— [(S) - 1 — amidino — 3 — piperidinylmethyl] -1,2,3,4-tetrahydro-2- (2-naphthylsulfonyl) -3-isoquinolinocarboxamide; (S) -Ν - [(RS) -1-amidino-3-piperidinylmethyl] -hexa-hydro-b- (2-naphthyl-sulfonamido) -g-oxo-1H-1-azepinabutyramide; (R) -N - [(S) -1-amidino-3-piperidinylmethyl] -a- (2-naphthylsulfonamido) -2,3-dioxo-1-indolinopropionamide; 4 (R) -2 - [[[(S) -1-amidino-3-piperidinyl] methyl] carbamoyl] 2- (2-naphthylsulfonamido) ethyl] oxanoic acid; (S) -N - [[(RS) -l-amidino-3-piperidinyl] methyl] -hexa-hydro-b-2-naphthyl · -sulfonamido-g-oxo-1 (2H) -azocinebutyramide; 4 2 (2RS, 4R) -1- [N - [[((S) -l-amidino-3-piperidinyl] methyl] -N - (2-naphthyl-sulfonyl) -L-asparaginyl] -4-methyl- 2-piperidine carboxylic; 4 '- [(R) -2 - [[[(S) -1-amidino-3-piperidinyl] methyl] carbamoyl] -2- (2-naphthylsulfonamido) ethyl] succinanilidic acid, characterized in that they are used correspondingly substituted starting compounds. 19.- Process for the preparation of pharmaceutical compositions that inhibit thrombin-induced platelet aggregation and fibrinogen coagulation in plasma, characterized by the fact that a therapeutically effective amount of a compound of formula I is converted into a galenic dosage form , prepared by the process according to claim 1, or a salt thereof.